Inflammatory Responses at Epithelial Cell Surfaces

E pithelial tissues line surface structures throughout the body and form a physical barrier that is impermeable to many infectious agents. In addition to providing an inert structural barrier, these tissues also play an active role in the initiation and regulation of innate immune defense mechanisms. In particular, the epithelium is a key player in the inflammatory response to infection or irritation. Injured epithelial cells release a variety of chemical factors that serve to inhibit pathogen replication and survival, attract cells of the immune system, and to promote healing of any damaged tissue following the clearance of pathogens. In the current issue of Viral Immunology, two articles focus on the induction of inflammatory cytokines in epithelial cells by influenza and human immunodeficiency virus (HIV). First, Song and colleagues investigate the response of human bronchial/tracheal epithelial cells to seasonal H1N1, 2009 pandemic H1N1, seasonal H3N2, or highly pathogenic H5N1 influenza virus infection. In each case, the viruses productively infected the cells and stimulated them to produce interleukin (IL)-8, interferon-γ-inducible protein-10, and growth-related oncogene-α. Furthermore, toll-like receptor-5 (TLR-5) was predominantly induced in cells infected with seasonal H1N1, pandemic H1N1, or H5N1 influenza virus, and TLR-3 was predominantly induced in cells infected with seasonal H3N2 influenza virus. These results suggest that TLR-5 and TLR-3 are involved in triggering the production of inflammatory mediators in influenza virus–infected respiratory epithelial cells. Second, Quaranta and colleagues investigate the infection and inflammatory responses of epithelial cells to HIV infection. The authors show that the accessory HIV-1 Nef protein significantly upregulates the expression of the HIV-co-receptor CXCR4 (but not the CCR5 co-receptor) on the surface of bladder, laryngeal, and intestinal epithelial cells. In addition, Nef also significantly upregulates IL-6 production by bladder and intestinal cells, and tumor necrosis factor-α (TNF-α) release by all three cell lines. These data indicate that Nef differently regulates co-receptor expression and cytokine secretion by epithelial cells, depending on the anatomical derivation of the cells.

While epithelial cells play a central role in innate immunity, many other cell types are involved in the induction of inflammatory responses. In this regard, Dhanushkodi and associates have analyzed the chemokine responses to Sindbis virus (SIN) in peripheral blood mononuclear cells (PBMCs). PBMCs derived from healthy volunteers were exposed to SIN in the presence and absence of lipopolysaccharide (LPS). The authors show that although the cells did not support SIN replication, the virus induced dramatic upregulation of the chemokines MCP-1, MIP1-α, and MIP1-β. SIN also induced secretion of IP-10, and this could be inhibited by co-culture with LPS. These data are important for understanding the pathogenesis of mixed infections and cross-talk between cellular pathways.

In addition to playing a critical role in inflammation and pathogen control, innate immune responses also regulate the adaptive immune response. Several articles in this issue of Viral Immunology focus on how adaptive immunity mediates control of a variety of infections. Peretz and colleagues investigate the mechanisms underlying slow HIV disease progression. This phenotype is associated with major histocompatibility complex (MHC) class I alleles such as B*57 and B*27, and is typically characterized by a polyfunctional profile in terms of T-cell cytokine secretion. Importantly the authors show that peptides restricted by both B*57/B*27 stimulated different responses in lymphocytes from slow-progressor versus progressor subjects. These findings suggest that functional heterogeneity within an individual is influenced by the restricting MHC allele, and that associations observed between slow disease progression and the expression of protective alleles is partly explained by the ability of these molecules to stimulate polyfunctional lymphocytes. T-cell responses also play an important role in viral clearance during infection with hepatitis B virus (HBV). Chen and colleagues have compared mini-plasmid vaccines to surface antigen of hepatitis B virus (HBsAg) adjuvanted with either CpG motifs or alum. Whereas the alum-based vaccine elicited a strong Th-2-biased response, the CpG-based vaccine induced a strong, and presumably more protective, Th-1-biased response. These data suggest that CpG-enriched plasmids may be a cost-effective approach for the development of therapeutic vaccines against HBV infection. A couple of articles in this issue focus on the specificity of adaptive immune responses that are elicited by infection. Robey and colleagues investigate CD8⁺ T-cell responses to Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma. KSHV is normally controlled by the immune system, but becomes problematic in immunosuppressed individuals with untreated HIV/AIDS. The authors identify two A*0201-restricted epitopes in proteins encoded by the late-lytic glycoproteins ORF28 and K8.1. They further show that these epitopes are recognized by 7.1% and 71.4% of individuals, respectively. These epitopes will be useful for further study of the CD8 response to KSHV. Another clinically relevant herpes virus is Epstein-Barr virus (EBV). Xue and colleagues analyzed the secondary structure and surface properties of the EBV LMP2A protein, and identified three peptides as potential candidates for linear B-cell epitopes. The authors go on to show that these three predictive epitopes defined immunodominant B-cell epitopes of LMP2A, and may be helpful in the design of diagnostic tools.

Finally, an article by Mavrouli and colleagues investigates the seroprevalence of pandemic H1N1 2009 influenza virus. As you will recall, the pandemic H1N1 2009 influenza A virus emerged in early 2009, spread rapidly across the globe, and was responsible for a considerable number of deaths. The need for surveillance of the immune status of populations led the authors to develop a virus-free ELISA that specifically recognizes the pandemic influenza virus antibodies in human sera. The assay takes advantage of synthetic peptides that are derived from the hemagglutinin and neuraminidase proteins of the virus, and was used to demonstrate a time-dependent increase of the prevalence of anti-H1-pep and anti-N1-pep IgG antibodies during the pandemic H1N1 outbreak in Greece. The authors point out that the assay could be used to distinguish individuals that are immune or susceptible to infection with the pandemic H1N1 virus, as well as for the monitoring of vaccination programs.