Scavenger Receptors in the Pathogenesis of Viral Infections

Abstract

Scavenger receptors (SR) are not only pattern recognition receptors involved in the immune response against pathogens but are also important receptors exploited by different virus to enter host cells, and thus represent targets for antiviral therapy. The high mutation rates of viruses, as well as their small genomes are partly responsible for the high rates of virus resistance and effective treatments remain a challenge. Most currently approved formulations target viral-encoded factors. Nevertheless, host proteins may function as additional targets. Thus, there is a need to explore and develop new strategies aiming at cellular factors involved in virus replication and host cell entry. SR-virus interactions have implications in the pathogenesis of several viral diseases and in adenovirus-based vaccination and gene transfer technologies, and may function as markers of severe progression. Inhibition of SR could reduce adenoviral uptake and improve gene therapy and vaccination, as well as reduce pathogenesis. In this review, we will examine the crucial role of SR play in cell entry of different types of human virus, which will allow us to further understand their role in protection and pathogenesis and its potential as antiviral molecules. The recent discovery of SR-B1 as co-factor of SARS-Cov-2 (severe acute respiratory syndrome coronavirus 2) entry is also discussed. Further fundamental research is essential to understand molecular interactions in the dynamic virus-host cell interplay through SR for rational design of therapeutic strategies.

Introduction

In 1970, Michael Brown and Joseph Goldstein first described the role of Scavenger receptors (SR) in the uptake of acetylated low-density lipoprotein (acLDL) and other polyanionic ligands, but not unmodified LDL (2,35). The term “scavenger receptor” was first used in 1981 (30). However, it was not until 1988 that the first SR was purified (58) and in 1990 cloned by Monty Krieger's group (57,102). Today 12 classes of SR (A–L) have been identified, based on the most recent consensus classification (96). SR vary in structure and recognize a large repertoire of ligands that define the broad range of functions they participate in, both physiologic and pathologic conditions (lipid metabolism, tissue homeostasis, pathogen recognition, atherosclerosis, inflammation, and autoimmune disorders).

Because their expression is predominant, but not limited to macrophages and dendritic cells (DCs), and their wide spectrum of ligands include pathogen-derived molecular patterns (PAMPs), as well as damage-associated molecular patterns, SR are considered to be an important subclass of the pattern recognition receptors (PRRs) of the innate immunity. Thus, SR are defined as “cell surface receptors that typically bind multiple ligands and promote the removal of nonself or altered-self targets” (95). Apart from the vital role these receptors play in innate immunity, they are also involved in adhesion, endocytosis, phagocytosis, transport, and signaling to help them fulfill their main function: elimination of degraded or harmful substances.

Notably, many SR have been identified either as receptors or co-receptors for viral internalization into host cells and as players modulating the immune response in the setting of diverse viral infections, including those by hepatitis C virus (HCV), Zika virus (ZIKV), Dengue virus (DENV), Chikungunya virus (CHIKV), herpesvirus, and respiratory virus. Understanding SR function in the scenario of viral diseases holds promise toward identifying therapeutic targets. Despite the advancements in antiviral therapy, increasing viral infections and associated mortality demand the identification of new targets for drug therapy (80). A clear example is the recent pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (44).

The small amount of viral proteins expressed by viral genomes represents a drawback to the identification of antiviral targets. Nevertheless, antiviral therapies may be aimed at host proteins involved in different stages of the virus life cycle. For example, the inhibitor of CCR5, an essential co-receptor for the entry of human immunodeficiency virus-1 (HIV-1) to host cells (75,89).

Other host-targeted proteins include Abl-family tyrosine kinase and the cellular growth factor ErbB-1. Inhibitors of these enzymes are able to block poxviruses replication (99,131). Also, inhibitors of enzymes involved in fatty acid synthesis have been shown to suppress DENV, CHIKV, and HCV infections, as lipids are essential to complete the viral replication cycles (43,52,123). In addition, monoclonal antibodies (mAb) that block host targets that mediate viral entry have been used successfully. mAb against tight junction proteins that serve as HCV receptors and inhibit infection have been developed (112).

Only few host-directed antiviral drugs have been FDA approved and most are based on interferon-γ (IFN-γ) to treat mainly chronic viral infections by HIV-1, human papillomavirus, hepatitis B virus (HBV), and HCV; others are in preclinical stages (17,62).

Antiviral strategies targeting cellular functions instead of viral proteins may minimize, although not impede, the development of drug-resistant mutants (61). Combination therapies that include host-targeted molecules and direct-acting antiviral agents are also used, showing synergistic effects in some cases (62). Likewise, modulation of the immune response elicited by viruses could also represent an approach to elude drug resistance, as well as prevent immune-mediated damage. SR previously known to participate in and enhance viral defense have been shown to also act as receptors for viral attachment and infection, suggesting its potential use as therapeutic targets to control or block viral internalization and alter pathogenicity.

This review will focus on some of the medically important viruses, its relation with SR and their potential use as antiviral targets. We will discuss some of the limitations and possibilities of generation of drug resistance against host-related molecules as antiviral targets (Table 1).

Table 1.

Virus–Scavenger Receptor Interactions

Virus family	Virus	SR (involved in entry/response)	Cell type or experimental model	Type of interaction	Outcome	Involved pathways	Reference
Adenoviridae	AdV-C5	SR-A	KC and J774, in vivo experiments	ND	SR inhibitors reduce uptake	ND	Xu et al. (130)
		SR-A	KC; J774 macrophages; in vivo experiments	ND	In vitro: Poly I reduces virus uptake; in vivo: enhanced viral particles in circulation, infection of other tissues and prevention of KC necrosis	ND	Haisma et al. (40)
		SR-A1	Macrophage-like Max Planck Institute cell	No binding or internalization	Reduced type I IFN production	ND	Stichling et al. (114)
		SR-A1.1	KC	Hexon regions HVR1, HVR2, HVR5, and HVR7 involved in SR interaction	Hepatocyte transduction	ND	Khare et al. (56)
		SR-A1.1	SR-A-transfected CHO cells; J774 macrophages; in vivo experiments	Recognition through the knob of the virus	Poly I and 2F8 reduced transgene expression and virus uptake; in vivo SR-A virus uptake by KC	ND	Haisma et al. (39)
		SR-A1	Human CD14⁺ monocytes; RAW 264.7 macrophages; PMA-THP 1 macrophages	Direct activation	Increased SR-A1 expression promotes virus entry, mediates the acLDL accumulation and ROS production	Activation of TLR3 expression, type I IFN, proinflammatory cytokines and chemokine production	Li et al. (66)
		MARCO	BMM; alveolar macrophages; alveolar macrophage-like Max Planck Institute cells	Direct activation	Type I IFN and IL-6 production after AdV escape from endosomes and cytosolic DNA sensor cGAS activation	Activation of NF-κB, IRF-3, and p38 pathways that leads to proinflammatory cytokine response	Maler et al. (71); Stichling et al. (114)
		MARCO	Macrophage-like Max Planck Institute cell	Direct interaction between hexon HVR1 and MARCO	MARCO enhances both viral binding and transduction	MARCO-mediated AdV5 entry exposes the virus to the cytosolic DNA sensor cGas for production of type I IFNs	Stichling et al. (114)
	AdV-A31 and AdV-B3, which have short HVR1 and/or lack the negatively charged residue clusters.	MARCO	Alveolar macrophage-like Max Planck Institute cell	No interaction detected, its transduction is independent from MARCO	ND	ND
	AdV-C2, AdV-D26, AdV-B35	MARCO	Alveolar macrophage-like Max Planck Institute cell	Direct interaction, but with less efficiency of uptake	ND	ND
Bunyaviridae	Hantavirus	sCD163 and CD163	Soluble receptor evaluated in human plasma and the transmembrane form detected in blood monocytes	ND	sCD163 is augmented in severe HFRS; potential marker of progression to severe disease, reflecting renal dysfunction. CD163 is increased in intermediate blood monocytes, probable anti-inflammatory role	ND	Wang et al. (124); Zhang et al. (136)
Filoviridae	Ebolavirus	sCD163 and CD163	Soluble receptor evaluated in human blood; transmembrane isoform expressed on KC	ND	High levels of both sCD163 in blood and CD163 in KC are associated with disease severity and fatal outcome. Potential markers of progression to severe forms of the disease	ND, but high levels of CD163 on liver macrophages in association with viral antigen, suggests that activation of KC contributes to pathogenesis in vivo	McElroy et al. (76)
Flaviviridae	HCV	SR-B1	Hepatocytes	Cofactor in virus internalization interaction with the viral E2 protein	SRB-1 provides a docking site for HCV particles and facilitates entry of the virus	Virions bind to SR-B1 in a process involving envelope type 2 glycoprotein and CD81 binding. This allows the virion to enter the cell through clathrin-mediated endocytosis.	Gerold et al. (33)
		SR-A1	Hepatocytes	Carrier of replication intermediates	Evidence suggests that SRA-A1 may mediate localized antiviral response in uninfected cells.	Induction of IFN synthesis, down modulatin of IFN response by repression of TRAF3	Lemon (64), Dansako et al. (20)
		SR-A1	Fulminant hepatitis model	Promotes fulminant hepatitis	Enhanced neutrophil netosis	Activation of TAK1 and ERK pathway	Tang et al. (118)
	DENV	SR-BI	U937 monocytes and Huh-7 cell line	DENV binds to apolipoprotein A-I in HDL; this complex interacts with SR-BI, increasing viral entry	Increased viral attachment and infectivity	ND	Li et al. (67)
	DENV	sCD163	Soluble receptor evaluated in human plasma	ND	sCD163 augmented in severe dengue and potential marker of progression to severe disease	sCD163 might participate in control of inflammation, reducing activation of T cells	Frings et al. (31); Högger and Sorg (45); Sarayu et al. (108); Ab-Rahman et al. (1)
	Zika virus	CD163	Hofbauer HC	ND	HC from the placenta show an M2 phenotype during Zika virus infection, which could promote chronic infection	ND	Jurado et al. (50); Rosenberg et al. (104)
Hepadnaviridae	HBV	SR-A1	Liver macrophages	ND	SR-A1 downmodulates HBV-triggered type I IFN response resulting in persistent viral infection	Acting as an adapter molecule, SR-A1 might repress TRAF3 activity upon viral stimulation	Xie et al. (128)
Herpesviridae	Herpes simplex virus 1	MARCO	Human keratinocytes and infection of mice	MARCO together with heparan sulfate proteoglycans mediates adsorption and infection	Direct binding of HSV-1 glycoprotein C to MARCO; MARCO KO mice have reduced susceptibility to HSV-1 infection	ND	MacLeod et al. (70)
	Herpes simplex virus 1	MARCO and SR-A1	Mice keratinocytes and fibroblasts; human keratinocytes	MARCO not involved in HSV-1 entry to cells	Poly I-mediated reduction of viral entry, but not dependent on interaction with MARCO	ND	Thier et al. (119)
	Human cytomegalovirus	SR-A1	Undifferentiated THP-1 monocytes	SR-A1-mediated endocytosis?	TLR3-mediated IFN-b and TLR9-mediated TNF-α production dependent on SR-A1 activation	SR-A1-dependent upregulation of IRF-3 and NF-κB p65	Yew et al. (133)
		SR-A1	Human smooth muscle cells	ND	Increased expression of SR-A1 upon infection	ND	Zhou et al. (138)
		SR-B1	HUVECs	ND	Increased expression of SR-B1 upon infection	ND	Guo et al. (37)
Orthomyxoviridae	IAV virus	MARCO	Alveolar macrophages	MARCO is not involved in IAV entry	MARCO reduces an early protective inflammatory response upon IAV infection, leading to increased viral replication and to diminished survival in mice. Thus, MARCO expression may be detrimental during IAV infection	MARCO mediates scavenging of oxidized phospholipids and postcellular debris, which trigger a proinflammatory response that enhances an early neutrophil recruitment to control viral replication.	Ghosh et al. (34)
Retroviridae	HIV	SR-B2 (CD36)	Human macrophages	HIV hijacks preexisting CD36⁺/CD9⁺ intracellular compartments for assembly and storage	CD36 mediates efficient HIV release to infect other cells like T lymphocytes	Possibly Gag oligomerization in compartments CD36⁺ induces recruitment and concentration of microdomains enriched with tetraspanins like CD9 and CD81 to elicit formation of membrane subdomains, which allow viral budding	Berre et al. (10)
Togaviridae	CHIKV	MARCO	KC in mice	ND	KC expressing MARCO participate in clearance of CHIKV preventing viral dissemination	ND	Carpentier et al. (14)
Togaviridae	CHIKV	SR-A1	Mouse blood cells, human thophoblasts, and BMM	SR-A1 binds the viral NSP1 protein	Inhibition of viral replication; reduced viral load	The complex between SR-A1 and NSP1 promotes assembly of the autophagy complex ATG5-ATG12-ATG16L1 that degrades the capsid protein	Yang et al. (132)

acLDL, acetylated low-density lipoprotein; AdV, adenoviruses; cGAS, cyclic GMP-AMP synthase; CHIKV, Chikungunya virus; DENV, Dengue virus; E2, envelope type 2; ERK, extracellular signal-regulated kinase; HBV, hepatitis B virus; HC, human cells; HCV, hepatitis C virus; HFRS, hemorrhagic fever with renal syndrome; HIV, human immunodeficiency virus; HUVEC, human umbilical vein endothelial cell; HVR, hypervariable region; IAV, Influenza A; IFN, interferon; IRF, interferon regulatory factor; KC, Kupffer cells; ND, not determined; NF-κB, nuclear factor-κB; SR, scavenger receptors; TAK1, transforming growth factor β-activated kinase 1; TLR, Toll-like receptor.

SR: Regulating Metabolism and Immune Responses

The different classes of SR include diverse members; we will include a brief description of the SR that have been shown to participate in virus-mediated recognition. In the first group, SR class A, SR-A1 or CD204 and SR-A6 or macrophage receptor with collagenous structure (MARCO) are the more thoroughly studied SR for their role in atherosclerosis. SR-A1 is expressed mostly on macrophages and DCs and is also involved in the maintenance of tissue homeostasis by clearance of modified self-components and apoptotic cells, in pathogenesis and in host defense against invading microorganisms (12). SR-A1 is alternatively spliced and exists in two isoforms, SR-A1 and SR-A1.1, with no functional differences and are thus collectively referred to as SR-A1. SR-A1 has been shown to participate in pathogenesis and repair mechanisms during viral infections (54,137).

The expression of MARCO is restricted to distinct populations of macrophages in the lungs, spleen, and lymph nodes. Most studies prove that MARCO plays a protective role in host defense against respiratory tract infections and pneumoccocosis, and has a regulatory effect on DC function and antitumor immunity (134).

Among the members of the class B SR, SR-B1 was the first identified receptor for high-density lipoprotein (HDL) and is one of the major carriers of cholesterol. It is similar to SR-B2, and can also transport modified LDL, native HDL, and very low-density lipoproteins (VLDL). SR-B1 is densely expressed in organs involving cholesterol metabolism, such as liver, adrenal glands, and gonads; this leads to belief that it is part of the regulation of cholesterol in the body and is an important receptor involved in HCV internalization (33).

SR-B2 also known as CD36, plays an important role in the recognition and endocytic uptake of oxidized phospholipids, modified LDL, apoptotic cells, and amyloid proteins, and is involved in the regulation of many aspects of inflammatory processes in atherosclerosis and Alzheimer's disease. It has also been called the “fatty acid translocase” because of its expression in adipocytes, hepatocytes, cardiomyocytes, and intestinal enterocytes. In these cells, SR-B2 mediates the binding and translocation of long-chain fatty acids, and in doing so, facilitates the intracellular accumulation of lipids (134). SR-B2 has been shown to facilitate HCV entry and replication through direct interaction with the viral protein envelope type 1 (E1) and functions as a specific co-receptor (18).

The SREC1 (SR expressed by endothelial cells-1) or SR-F1 was identified as an endothelial receptor for LDL, but recent studies show the expression of this receptor in phagocytic cells and its involvement in the clearance of apoptotic cells (86). SR-F1 has been shown to cooperate with Toll-like receptor 2 (TLR2) to induce activation of myeloid cells during HCV infection (8).

CD163 belongs to class I and is expressed on the plasma membrane of monocytes/macrophages and as a soluble form (sCD163) after proteolytic cleavage by metalloproteinase ADAM17, which releases the ectodomain (25). The most studied function of CD163 is as receptor for hemoglobin–haptoglobin complexes. Nevertheless, as other SR, CD163 has been shown to have other functions. CD163 acts as a pathogen recognition receptor and its expression on macrophages is associated with the regulation of the inflammatory response: anti-inflammatory signals tend to induce expression of CD163, while proinflammatory signals suppress it (121).

SR and Viral Hepatitis

Undoubtedly, the best-studied SR in the setting of viral hepatitis is SR-B1. It is abundantly expressed in liver, operates in several metabolic processes, and participates in the pathogenesis of diverse conditions, including the development of HCV infection (33). This infection is closely related to metabolic processes, including cholesterol transport. Cholesterol is required for maintenance of plasma membrane fluidity and integrity and for many cellular functions. Cellular cholesterol can be obtained from lipoproteins in a selective pathway of HDL-cholesteryl ester (CE) uptake. SR-B1 is a cell surface HDL receptor that mediates HDL-CE uptake (109).

During HCV infection, initial viral attachment is mediated by the low-density lipoprotein receptor (LDL-R), the protein responsible for transporting most of the cholesterol in plasma. At least six additional host entry factors, including, CD81, the tight junction proteins claudin 1 (CLDN1), occluding (OCLN) (135), receptor tyrosine kinases (69), the Niemann-Pick C1-like 1 cholesterol absorption receptor (106), and SR-B1, are important for particle internalization. In addition to providing a docking site for HCV particles, SR-B1 facilitates entry of the virus into the hepatocytes (83,94).

HCV entry is mediated by the E1 and envelope type 2 (E2) viral glycoprotein attachment to cellular receptors. Initial attachment of HCV virions to the cell surface is mediated by interactions with heparan sulfate glycosaminoglycans and LDL-R. Virions subsequently bind to SR-B1 in a stepwise process involving E2 glycoprotein interactions (7,21,139). Binding to SR-B1 induces binding of the E2 protein to CD81 in an undetermined mechanism (92,139). The interaction with CD81 triggers a signaling cascade promoting the recruitment of actin to the cell surface and further trafficking of the virion/receptor complex to the cell-cell tight junctions (72).

Within the tight junctions, interactions with CLDN1 and OCLN allow the virion to enter the cell through clathrin-mediated endocytosis (135). Specific E2 amino acid residues involved in CD81 binding have been identified (55,59), while the interaction between E2 and the SR-B1 is complex and involves accessory interactions with lipoproteins on the virion, as well as direct interaction with the E2 protein thought to be mediated by the 27-amino-acid sequence at the amino (N) terminus-denominated hypervariable region 1 (HVR1) (59).

The generation of neutralizing antibodies represents a protective strategy in host immunity and several envelope glycoprotein domains have been shown to play pivotal roles in HCV entry and neutralization. These antibodies target epitopes within the HVR1 (24) and were initially identified in a study of transplant recipients in which the HCV viremia was lower in patients receiving immunotherapy with anti-HBV immunoglobulins contaminated with anti-HCV immunoglobulins, compared to patients whose therapy did not include anti-HCV antibodies (29). Later, functional analysis and neutralization experiments using sera from chronically HCV-infected patients have demonstrated that host-neutralizing responses target viral entry at a step after initial HCV binding, while the presence of neutralizing antibodies correlates with protection from HCV (82).

Without effective vaccines available against HCV, multiple efforts have been conducted, given the urgent need to contain a virus epidemic (49). One major challenge in the development of a vaccine and effective antiviral therapies is the genetic diversity of the virus, with seven major genotypes and many characterized subtypes. Thus, a global therapy must be effective against all HCV genotypes. Mutations in HVR1 of E2 can result in escape from broadly neutralizing mAb (101) and some of these mutations alter virus interactions with the entry receptor SR-B1 (24). This is consistent with the finding that HCV can evade the neutralizing antibody response.

In vivo experiments with chimeric mice have demonstrated that prophylactic administration of anti-SR-B1 antibodies protects from different HCV genotypes (77). However, as mentioned previously, different HCV genomic variants carrying changes in their E2 glycoprotein are resistant to SR-B1 blocking therapy in cell culture (5,15,16). Nevertheless, a humanized mouse model for infection with HCV variants resistant to SR-B1 antibody therapy in vitro has shown a prophylactic and postexposure antiviral effect by the combination of mAb1671, an anti-SR-B1 mAb, with HLD and VLDL lipoproteins, supporting the effectiveness of SR-B1 inhibition (74,122).

This is in accordance with the fact that, in addition to SR-B1 involvement in HCV entry based on its ability to interact with HCV E2 glycoprotein, SR-B1 physiological lipid transfer function is also important in viral internalization. Indeed, anti-HCV activity in vitro has been reported for small-molecule inhibitors of SR-B1-mediated CE lipid uptake (117) and clinical safety for SR-B1 inhibitors has been reported (115). Therefore, SR-B1-trageting approaches may be critical in the design of vaccine candidates for HCV and as an alternative in terms of costs to currently available antivirals for this virus. Furthermore, taking into account the role of SR in HBV infection (see end of section), SR-based therapeutic strategies may also be useful in the setting of HCV and HBV coinfection.

SR-A1 is another receptor involved in HCV-related pathogenesis. As mentioned previously, SR-A1 binds to and facilitates the cellular import of a broad range of ligands, including acLDL, bacterial constituents, and both single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) (93). While the expression of SR-A1 has been considered previously to be restricted to cells of myeloid origin, primarily macrophages, recent data suggest that members of the class A SR family are expressed more ubiquitously and are present on the surface of a variety of cell types (22).

A prominent role for SR-A1 in viral infections has been evidenced in mice deficient in SR-A1, which results in an increased susceptibility to infection with herpes simplex virus 1 (HSV-1) (116). In addition, SR-A1 is required for induction of Toll-like receptor 3 (TLR3)-mediated signaling in monocytes exposed to human cytomegalovirus (HCMV) (133).

During HCV infection, this positive ssRNA-enveloped virus produces dsRNA replication intermediates. The viral RNAs are recognized as PAMPs by several classes of cellular PRRs, including retinoic acid-inducible gene I-like helicases and TLR3. TLR3 senses dsRNA and initiates signaling only from within late endosomes (48).

Evidence in vitro showed that uninfected hepatocytes are capable of sensing HCV infection in adjacent cells and that SR-A1 mediates this response by acting as a carrier of replication intermediates from the extracellular milieu to endosomally expressed TLR3 in uninfected cells. Since uninfected hepatocytes are not subject to the mechanisms that viral proteins have evolved to disrupt the induction of IFN responses (64), the engagement of TLR3 by viral RNAs results in the induction of IFN synthesis.

This SR-A1-TLR3-mediated mechanism may establish a localized antiviral response in adjacent, uninfected cells that restrict the replication of virus as identified in cell cultures (20). Moreover, in a murine model of viral hepatitis, SR-A1 has been shown to promote the pathogenesis of virus-induced fulminant hepatitis by enhancing induction of neutrophil NETosis through activation of transforming growth factor β-activated kinase 1 and extracellular signal-regulated kinase in neutrophils with subsequent complement activation (118). Thus, targeting SR-A1 may be employed as antiviral and immunotherapy strategy in the setting of viral hepatitis.

As mentioned above, SR-A1 acts as an innate PRR and plays a critical role in host defense against foreign microbial infections by recognizing and clearing pathogens or modified self-molecules (87,93). SR-A1 also serves as an adaptor molecule or coreceptor for TLRs (20) and it has been shown to act as a carrier, mediating dsRNA entry and delivery to the intracellular dsRNA sensors (22,68). Tumor necrosis factor receptor-associated factor (TRAF) family mediates signal transduction initiated by numerous PRRs (129). In particular, TRAF3 controls type I IFN production in response to viral infections (38).

The control of type I IFN is mediated at the transcriptional level and transcriptional factors, including nuclear factor-κB (NF-κB) and interferon regulatory factors, play crucial roles (46). Ubiquitination is a post-translational regulatory mechanism in the control of virus-induced IFN response (73). K48 chain-linked polyubiquitination of TRAF3 causes its early proteasome-dependent degradation, resulting in the enhancement of cellular NF-κB responses, whereas K63 chain-linked polyubiquitination mainly controls the downstream signals leading to the production of type I IFNs (120). Recently, data from loss and gain of function studies reveal that SR-A1 downmodulates HBV-triggered type I IFN response by repressing TRAF3 activity upon viral stimulation.

Acting as an adapter molecule, SR-A1 affects the conjugation of K63-linked ubiquitin chains to TRAF3, suppressing TRAF3 ubiquitination, resulting in a decreased production of type I IFN and consequent persistent viral infection (128). Therefore, SR-A1 influences the control of the cellular antiviral response against HBV infection. This is consistent with the previously reported SRA^−/− mouse model that shows higher susceptibility to infection with HSV-1 (116). Indeed, lower levels of HBV DNA are found in SRA^−/− and this is associated with a higher IFN type I production compared with wild-type controls (128), underscoring a pivotal role of SR-A1 in modulating the innate antiviral immunity.

Moreover, in a replication-defective recombinant adenovirus type 5 expressing ovalbumin model under the HCMV (AdOVA) to establish hepatotropic infection, Labonte et al. found an increased expression of SR-A1 in liver macrophages at a point time coinciding with viral clearance and the beginning of tissue repair. In this model, an impaired expression of M2 genes consistent with a loss of ability to become activated is observed in liver macrophages recovered from SR-A1^−/− mice and adoptive transfer of SR-A1-expressing macrophages into knockout mice protected against viral induced tissue damage through a mammalian target of rapamycin-mediated proposed mechanism (63).

Altogether, these findings suggest a crucial role for SR in controlling immune responses to viral infection and tissue repair in the setting of liver disease and strongly support that understanding SR-induced pathways and their involvement as modulators of the immune response may open avenues into improve therapies against viral hepatitis.

SR in Dengue, Zika, and Chikungunya Infections

Arboviral diseases like Dengue, Chikungunya, and Zika are currently recognized as global public health threats because of their potential to produce high rates of morbidity with life-threatening severe cases, incapacitating polyarthralgias and severe neurological damage. Emergence of ZIKV in Latin America allowed identification of particular biological properties poorly recognized in flavivirus, such as the broad cellular tropism, persistence in immune-privileged sites, and sexual transmission, representing new challenges for fundamental and clinical research (91,127).

Dengue virus

DENV is an enveloped, positive-sense ssRNA virus, member of the Flaviviridae family, which is transmitted in tropical and subtropical regions by mosquitoes of the genera Aedes. According to the annual estimated incidence, DENV produces from 284 to 528 million infections worldwide, of which, 96 million represent symptomatic diseases (41,126a).

There are four different serotypes of DENV globally distributed and all of them are present and co-circulating in many countries in Latin America (98). DENV has tropism for monocytes, macrophages, Langerhans cells, keratinocytes, endothelial and dermal DCs (11,23). The virus exploits different cell surface molecules that function as attachment factors and viral receptors, including DC-SIGN, CD14, glycosaminoglycans, Langerins, TIM1, AXL, and the mannose receptor, whereas viral entry is also facilitated by Fc gamma and complement receptors when the virus forms complexes with heterologous antibodies (9,78,88). Thus, DENV recognizes a broad variety of molecules, possibly in a serotype-specific manner and according to the diversity of cells susceptible to infection (19).

The participation of SR-B1 in DENV infection of monocytes has also been described. Apolipoprotein A-I (Apo-AI) is the major protein component in HDL, which is recognized by SR-B1. DENV exposed to human serum directly binds Apo-AI, which, independently of its state of lipidation, increases viral infectivity up to sixfold in a dose-dependent manner. SR-B1 knockdown by siRNA reduces infectivity in monocytes and liver cell lines when exposed to the preformed DENV–Apo-AI complexes, indicating Apo-AI functions as a bridge between DENV and this SR, facilitating cell entry (67).

On the other hand, expression of class I SR CD163 is altered in DENV infection. As mentioned above, CD163 is expressed as membrane-bound and soluble isoforms. sCD163 is significantly increased in serum from Dengue patients with respect to healthy subjects (108). Moreover, sCD163 is significantly augmented during defervescence in patients with secondary DENV infection and in patients with severe Dengue compared to mild Dengue fever patients, making it a potential marker of progression to severe forms of the disease (1,108).

Although it has not been determined whether sCD163 is involved in Dengue pathogenesis or is a product of macrophage activation under inflammatory conditions, the fact that this molecule is increased in late phases of acute inflammation, in chronic inflammation, and in wound healing tissues suggests a role as an anti-inflammatory factor (31). Actually, sCD163, but not the membrane-bound molecule, reduces activation and proliferation of primary human T lymphocytes (31,45).

Interestingly, sCD163 is not only increased in severe DENV infection but also in other viral hemorrhagic fevers, like Ebola and hemorrhagic fever with renal syndrome (HFRS) caused by Hantaviruses (76,124,136). It is worth mentioning that subjects with severe and critical HFRS display 2- and 2.5-fold increase in plasma sCD163 levels, respectively, supporting its valuable use as a biomarker to predict severity of viral hemorrhagic diseases (124).

Zika virus

ZIKV is another flavivirus closely related to DENV that produces mostly asymptomatic infections (∼80%), whereas those that are symptomatic are generally benign and self-limiting. However, infections occurring during the first trimester of pregnancy are highly associated with congenital malformations, including microcephaly. Progressive vision and hearing loss have also been described in infants exposed to the virus during gestation, even in the absence of microcephaly (3,6).

ZIKV infects the placenta and it is subsequently transmitted to the developing fetus, producing neurological malformations. Hofbauer cells in the chorionic villi of the placenta have features of alternatively activated macrophages expressing high levels of CD163 during ZIKV infection and are the main targets of the virus (50,104). Even though CD163 has not been described as a ZIKV receptor, it might play an important role in the anti-inflammatory response, promoting a more chronic outcome (26).

Chikungunya virus

CHIKV is an alphavirus introduced in the Americas in 2013, which showed a rapid spread in almost 50 countries, causing over 2 million of suspected cases of acute illness with polyarthralgias and arthritis, which can persist in some individuals for months to years (113). The innate immune response associated to viral control has been of interest to understand transmission and pathogenesis of CHIKV infection in vertebrate hosts. In this regard, Carpentier et al. showed that phagocytic cells, particularly liver Kupffer cells (KC), but not spleen macrophages, are essential for clearance of alphavirus in blood.

When KC are depleted in mice, CHIKV is detected for longer periods in circulation and it is distributed at higher amounts in spleen and lungs, supporting the relevant role of this cell population to control viral dissemination. Importantly, clearance is not dependent on opsonins like antibodies or the complement factor C3. Instead, viral elimination depends on the expression of MARCO on liver macrophages, as demonstrated by treatment with competitive inhibitors as polyinosinic acid (poly I) I and dextran sulfate, as well as in mice with a MARCO^−/− phenotype (14).

In addition, SR-A1 is also associated with the control of CHIKV replication in mice and in vitro, in primary cells like bone marrow-derived mouse macrophages and human trophoblasts by means of autophagy. The mechanism related to inhibition of viral replication was studied after observing that SR-A1 is upregulated in mice blood cells following CHIKV infection and such increase inversely correlated with the viral loads; in contrast, SRA^−/− mice displayed elevated viremia with respect to wild-type mice.

The proposed antiviral mechanism indicates that initially, SR-A1 binds the viral NSP1 protein and then interacts through its cytoplasmic tail, with the autophagy complex ATG5-ATG12-ATG16L1, which degrades the viral capsid protein, limiting CHIKV replication (132). Thus, SR have been mainly described as PRRs to restrain alphavirus infection instead of participating in adhesion and/or viral entry.

Herpesvirus and SR

Herpes simplex virus 1

HSV-1 is an alpha-herpesvirus and consists of linear double-stranded DNA (dsDNA), enclosed by a capsid surrounded by different tegumental viral proteins and finally covered by an envelope that has several glycoproteins involved in cell attachment, fusion with the cell membrane, and delivery of the viral content into the host cell. Four viral glycoproteins (glycoprotein [g]B, gD, gH, and gL) are sufficient for membrane fusion and viral content delivery. gD binds to nectin-1, which acts as a major receptor for HSV-1 or herpesvirus entry mediator, a member of the tumor necrosis factor receptor superfamily that acts as an alternative receptor (32,81). On the other hand, both gB and gC bind to heparan sulfate proteoglycans on the cell surface.

These glycoproteins are not essential for infection but in their absence, infection is reduced (119). Usually, HSV-1 first infects epithelial cells and then spreads to sensory neurons, but is able to infect a wide range of cell types. The high infection efficacy of HSV-1 is also reflected in the high prevalence (40–80%) in the human population (51) and may be partially due to different host receptors being involved in viral recognition, which are present in diverse cell types.

Mice deficient in SR-A1 show higher susceptibility to infection with HSV-1 (116). However, the role of SR in cell entry is elusive, MacLeod et al., showed that MARCO enhances adsorption and infection of keratinocytes through interaction with gC. These findings are supported by competition experiments using the SR ligand poly I, overexpression of MARCO that stimulates HSV-1 infection of keratinocytes, and the use of knockout mice showing that lack of MARCO expression results in less susceptibility to HSV-1 infection. In addition MARCO could play a role in HSV-1-induced pathogenesis (70).

On the other hand, a recent article showed that, although MARCO seems to mediate adsorption of HSV-1 to epithelial cells, this receptor is dispensable for entry into murine epidermal keratinocytes and dermal fibroblasts, as shown in MARCO knockout cells. Instead, the SR agonist poly I efficiently reduces the number of infected cells, probably by interfering with viral adsorption. The authors show that MARCO and SR-A1 are not the direct targets of the polyanionic ligand, as HSV-1 infection occurs in the absence of both class A SR (119).

The possibility of other SR being involved warrants further analysis. SR-A5 is a recently discovered member of class A SR, with high structural similarity to SR-A1 and MARCO. Importantly, it binds polyanionic ligands and is primarily expressed in epithelial cells and fibroblasts in the connective tissue of several organs, including skin (47,85). The question arises, could SR-A5 serve as a receptor of HSV-1?

Class A SR expressed in macrophages are important in host defense as they bind dsRNA and enable its interaction with TLR3 to promote an antiviral state (22,68). Nevertheless, their involvement in enhancing infection warrants further research to elucidate its potential as a therapeutic target in HSV-1 infection and determine if the interactions with SR benefit the host or the virus. Moreover, rapid internalization by SR may also function to modulate or prevent innate antiviral immune responses initiated by other PRRs, which could prove beneficial for viral replication.

Human cytomegalovirus

HCMV a betaherpesvirus 5, is a dsDNA virus with an infection rate of 80–100% of the human population from childhood to adulthood and establishes latent infections with the possibility of reactivation at any time point (36). HCMV is an important pathogenic factor involved in atherosclerosis. In addition to its role in activation of platelets and smooth muscle cells, damage to endothelial cells, and enhancement of the inflammatory response, HCMV promotes lipid accumulation in atherosclerotic plaques (65,107).

Infection with HCMV upregulates SR-A1 expression in human vascular smooth muscle cells. This is accompanied by an increase in the uptake of modified LDL. Furthermore, using a model of abortive HCMV infection without the associated cytopathic effects in rat smooth muscle cells, the authors showed expression of immediate early genes alone is sufficient to upregulate modified LDL uptake (138).

In a recent article, Guo et al. showed that HCMV infection of human umbilical vein endothelial cells (HUVECs) inhibited the expression ssDNA-binding protein (SSBP1), at both the mRNA and protein levels. This in turn resulted in lipid accumulation in HUVECs and the concomitant upregulation of several genes involved in lipid metabolism and transport, including SR-B1 (37). Thus, regulation of SR-A1 and SR-B1 function, as a therapeutic intervention, could help control the development of atherosclerosis that accompanies HCMV infection and contributes to the pathology induced by the virus.

SR in Respiratory Viral Infections

Adenovirus C5 infection

With more than 100 serotypes of human strains, classified into 7 species (A–G), adenoviruses (AdV) are capable of invading a broad range of tissues, including the respiratory tract (AdV-B, AdV-C, and AdV-E), the conjunctiva (AdV-C and AdV-D), and the urinary (AdV-B) as well as the gastrointestinal tracts (AdV-A, AdV-F, and AdV-G), causing self-limiting infections. AdV are nonenveloped dsDNA viruses that use different receptors and facilitators to infect a wide number of different cell types. AdV-B, AdV-C, and AdV-E produce respiratory infections, with AdV-C5 being highly prevalent in 30–80% of the human population and the most extensively studied, since it has also been used as delivery vector due its large genome capacity (4). Moreover, replication-deficient AdV vectors have also been used for vaccination against a broad spectrum of diseases (103).

Studies using MARCO-transfected cells, MARCO-deficient cells, as well as SR-blocking antibodies showed that MARCO enhances AdV-C5 and recombinant AdV vector internalization by murine alveolar macrophages (AM) and AM-like primary cell line (Max Planck Institute cells) in cooperation with other AdV receptors. Although human MARCO facilitates AdV-C5 entry to transfected cells, it is less efficient than the murine ortholog-transfected cells (114). Thus, extrapolation of virus-SR interactions using mouse cells shows some limitations for human studies.

MARCO-mediated entry of AdV results in cytoplasmic translocation and activation of the cytoplasmic DNA sensor cyclic GMP-AMP synthase in AM, which results in the production of proinflammatory cytokines like IL-1α, IL-6, and type I IFN shortly after SR recognition of the virus (71,114,140). Indeed, MARCO-expressing macrophages subtypes (peritoneal macrophages, AM, and marginal zone splenic macrophages, but not bone-marrow-derived macrophages) show a higher AdV sensitivity (27), suggesting that blockade of MARCO could reduce immune-mediated responses associated with AdV internalization. MARCO also serves as a receptor for AdV-C2, AdV-D26, and AdV-B35, while AdV-A31 and AdV-B3 were shown to be independent of MARCO expression (79,100,114)

MARCO participation occurs through direct virion binding of the negatively charged HVR1 of the viral hexon protein, which is implicated in the interaction of AdV-C5 to SR-A1 (56,114). Acidic residues in this domain seem to interact with the SR. Some AdV strains lack the acidic residues or have a short HVR1 domain (AdV-B3 and AdV-A31) and do not bind to MPI cells, suggesting that these residues are important for SR interactions. However, AdV-D26 lacks the acidic residues, but its interaction with MPI cells correlates with MARCO expression (114). Thus, other regions in the viral proteins contribute to SR binding.

SR-A1 and its splice variant SR-A1.1 are involved in AdV-C5 uptake and cytokine production. Haisma et al. showed that poly I inhibited KC AdV-C5-induced transduction in macrophages in vitro and increased circulating viral load, as well as reduced KC necrosis in vivo, suggesting that SR are the main mechanism for AdV-C5 clearance in vivo (39,40,130). Moreover, treatment with a specific SR-A1 antibody (2F8) reduced AdV-C5 uptake and viral gene expression in the J774 macrophage line and primary KC (39). In contrast, Stichling et al. found that SR-A1 participates in the AdV-C5-induced cytokine response in MPI cells, but no contribution of SR-A1 in AdV-C5 binding and internalization (114).

This discrepancy may reflect the differential activation of SR-dependent signaling pathways in different macrophage subpopulations. Moreover, different macrophage subtypes may use different SR in the interaction with AdV-C5. For example, SR-F1 in KC and endothelial cells interacts with AdV-C5, although these receptors seem to participate less in AM (90). Thus, SR interactions have implications for AdV-based vaccination and gene transfer technologies. Inhibition of SR could reduce adenoviral uptake and improve gene therapy and vaccination, as well as reduce AdV pathogenesis.

SR may have dual roles in the interaction of AdV, on one hand, facilitating entrance of the virus, and on the other initiating an inflammatory response to limit virus replication and spread. AdV-C5-infected subjects show increased expression of SR-A1 in circulating CD14⁺ monocytes accompanied by increased level of lipid uptake and reactive oxygen species production (66), underscoring the complex interaction between viruses and SR.

Influenza A virus

Influenza viruses are enveloped viruses that belong to the Orthomyxoviridae family, with 7 or 8 RNA segments that codify for 10 or 11 proteins and are divided into 3 types: A, B, and C. Influenza A (IAV) and B viruses are principally responsible for seasonal epidemics. Currently IAV is considered to have pandemic potential (53). As previously mentioned, SR expressed in macrophages participate in resistance to different virus, including AdV (39,130), HSV-1 (116), and HCMV (133). Instead, studies in vitro show that MARCO is not involved in IAV internalization by murine AM in vivo and its presence results in a deleterious outcome. MARCO knockout mice exhibit higher survival rates upon IAV infection than wild-type mice. MARCO expression suppresses the protective early immune response in the lungs by eliminating proinflammatory oxidized lipids.

This results in higher susceptibility to IAV due to lack of neutrophil infiltration in early stages of infection (34). The importance of MARCO in the early innate response is highlighted by a study of transcriptional responses in monocytes showing that MARCO was among the genes displaying large population differences upon infection with IAV (97). Therefore, regulating the function of MARCO at specific time points of infection may result in the control of IAV infection.

Severe acute respiratory syndrome coronavirus 2

The ongoing SARS-CoV-2 pandemic has impacted the lives of people worldwide. SARS-COV-2 causes coronavirus disease 19 (COVID-19) responsible for high morbidity and mortality (84). Although vaccines have proven effective and reduce severity of COVID-19 (60), the emergence of new variants highlights the importance of understanding the underlying mechanisms of viral cell entry to develop new therapeutic agents.

To infect cells, SARS-CoV-2, an enveloped positive sense ssRNA virus, binds to the angiotensin-converting enzyme 2 (ACE2) through the S1 subunit of the viral spike protein (S protein), and then the transmembrane protease serine 2 (TMPRRS2) cleaves the S2 subunit allowing fusion of the viral envelope and the cell membrane. As a consequence, the viral genome is released into the cytoplasm and the replication-transcription complex (RTC) is synthesized from the nonstructural proteins. The RTC synthesizes a copy of the original positive ssRNA in a negative sense, which leads to the generation of new viral particles (42).

Like many other viruses, SARS-CoV-2 uses co-receptors to enhance infection of cells. In addition to neuropilin-1 (13) and the still debatable CD147 (28,111,125), SR-B1 has been shown to boost viral uptake into ACE2-expressing cells by increasing virus attachment. SR-B1 is co-expressed with ACE2 in multiple tissues, including the lung and small and large intestines. However, the S1 subunit does not bind directly to SR-B1. Instead, it seems that HDL serves as a bridge between the S1 subunit and SR-B1. Indeed, the S1 subunit sequence was found to contain six cholesterol recognition amino acid consensus (CRAC) motifs adjacent to the inverted cholesterol recognition motifs coined as CARC and is able to bind cholesterol, HDL, or its components.

HDL increased cell attachment, entry, and replication of SARS-CoV-2 (126). This is in agreement with the participation of SR-B1 in HDL endocytosis and cholesterol efflux (110). Thus, SR-B1 is proposed to serve as a co-factor for SARS-CoV-2 infection. Moreover, two SR-B1 inhibitors, ITX5061 and block lipid transport-1, hinder SARS-CoV-2 infection stimulated by HDL (126). Moreover, ITX5061 has been used in humans and shown to have antiatherogenic effects upon partial SR-B1 inhibition (74) and to limit HCV evolution in liver transplant patients (105).

These data suggest the SR-B1 inhibitor could have potential benefits against SARS-CoV-2 by transiently blocking SR-B1. Thus, more studies are needed to elucidate the molecular mechanisms involved in SR-B1 facilitation of viral entry.

CRAC motifs are also present in proteins from other viruses, such as in the HIV matrix protein p17 that participates in virus entry through lipid rafts in the cell and in NS5A of HCV involved in replication in the endoplasmic reticulum, as well as in the M1 matrix protein of IAV. The role of these proteins in cell cholesterol depletion and its negative effects on cell function during virion formation have been documented. Thus, the participation of SR in this process warrants further analysis to determine if inhibition of the receptors aids in the pathogenesis of viral infections.

Conclusions

SR indeed represent possible targets for antiviral therapy. SR participate in viral entry, attachment, replication, as well as in dissemination of viral particles and even in determining viral-induced pathology, such as cellular function in cholesterol-depleted cells and the cytokine response (Fig. 1), in addition to their participation in the interplay of viruses with different components of the host lipid metabolism and as markers of severe disease.

FIG. 1.

SR and virus interactions. SR have the ability to facilitate phagocytosis or endocytosis in a process mediated by PRR signals. (a) SR-B1 and (b) SR-B2 are mainly expressed in tissues involved in the metabolism of fatty acids; their ligands are HDL and LDL, respectively. Both receptors are involved in an entry and replication pathway for HCV. (c) SR-A6 expressed in macrophages helps against infections of pathogens such as CHIKV. (d) SR-A1 whose ligands include LDL, ssRNA, and dsRNA molecules is associated to an antiviral response against HCV, CHIKV, and HSV-1. (e) SR-B1 mediates DENV internalization into macrophages when virions are in complex with APO-AI. This mechanism is associated with a higher degree of infection. (f) sCD136 in serum is related to an anti-inflammatory effect during DENV infection. (g) Membrane-bound CD136 is expressed in alternatively activated macrophages that regulate inflammation. CD136⁺ Hofbauer cells from the chorionic villi are targets for ZIKV. The anti-inflammatory environment might promote chronic viral infection. (h) Strategies for blocking certain receptors such as SR-B1 have been proposed as an antiviral therapy. CHIKV, Chikungunya virus; DENV, Dengue virus; dsRNA, double-stranded RNA; HCV, hepatitis C virus; LDL, low-density lipoprotein; PRR, pattern recognition receptor; ssRNA, single-stranded RNA; ZIKV, Zika virus.

Participation of SR at any stage of the virus replication cycle renders them potential targets for antiviral therapy. SR are even involved in viral release and spread to uninfected cells. For example, Berre et al. described that HIV-1 hijacks preexisting SR-B2⁺/CD9⁺ intracellular compartments in macrophages for assembly and storage. In such compartments, SR-B2 expression is necessary for efficient release of HIV-1, as observed in macrophages treated with siRNA against SR-B2 and monoclonal anti-SR-B2 antibodies, which tethers the virions at the intracellular compartment reducing up to 80% of virus release. Remarkably, monoclonal anti-SR-B2 antibodies inhibited HIV-1 transmission from infected macrophages to T lymphocytes, suggesting that anti-SR-B2 may be used to boost antiretroviral therapy, targeting viral reservoirs established in macrophages (10).

Virus-SR interactions could imply both beneficial and harmful effects. On one hand, SR involvement in triggering an efficient and regulated innate immune response to the viral insult, and on the other, a mode of entrance and dissemination exploited by viruses. Targeting SR to modulate the immune response remains a challenge and should be aimed additionally at preventing the development of chronic infections (Table 2).

Table 2.

Antiviral Potential of Scavenger Receptors

Virus	SR	Potential antiviral molecule/therapeutic effect	Reference
HCV	SR-A1	Potential inhibition of virus-induced fulminant hepatitis	Tang et al. (118)
HCV	SR-B1	ITX5061/inhibition of infection	Syder et al. (117)
HCV	SR-B1	Anti SR-B1 1671 mAb alone or in combination with lipoproteins/inhibition of infection	Vercauteren et al. (122)
HCV	SR-A1	Anti SR-B1 mAb/inhibition of infection and spread	Meuleman et al. (77)
HBV	SRA-1	Indirect effect might influence the control of cellular antiviral response	Xie et al. (128)
DENV	SR-B1	Potential inhibition of infection by DENV-ApoI complexes	Li et al. (67)
DENV	sCD163	Potential marker of severe disease	Ab-Rahman et al. (1); Sarayu et al. (108)
CHIKV	MARCO, SR-A1	Potential enhancement of virus elimination	Yang et al. (132)
AdV	MARCO, SR-A1	Potential improvement of gene therapy and vaccination	Haisma et al. (39)
IAV	MARCO	Potential control of infection at specific time points	Ghosh et al. (34)
SARS-CoV-2	SR-B1	ITX5061 and BLT-1/inhibition of infection	Wei et al. (126)

ApoI, apolipoprotein I; BLT-1, block lipid transport-1; mAb, monoclonal antibodies; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Currently, during viral hepatitis, clinical safety for SR-B1 inhibitors and prophylactic administration of anti-SR-B1 antibodies have been described. In addition, an immunomodulatory role of SR-A1 acting as an adapter molecule, which modulates HBV-triggered IFN response, has been proposed. Thus, in the setting of viral hepatitis, SR promote antiviral effects either by modulating virus internalization or by regulating the host cellular antiviral immune response.

In addition, manipulation of SR could aid not only in the regulation of infection outcomes but also in developing more efficient ways to use adenoviral vectors as antiviral agents in gene delivery and vaccination schemes. Understanding the exact interaction of SR with the virus and cellular components, as well as the signaling pathways involved is important in manipulating SR as antiviral strategies. Further basic research is essential to understand molecular interactions in the dynamic virus-host cell interplay for rational design of therapeutic strategies based on drugs, mAb, and natural ligands or bioactive compounds.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by grant IN208420 from Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT), Dirección General de Asuntos del Personal Académico (DGAPA), and Universidad Nacional Autónoma de México (UNAM), Mexico.

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