Abstract
C
Human coronavirus infections have been reported since the 1960s, initially by HCoV-229E (8,19). However, only in 2002 and later, in 2012, coronaviruses attracted worldwide attention with the emergence of SARS-CoV and MERS-CoV, respectively (3,29). SARS-CoV circulated between November 2002 and July 2003, infecting 8,098 individuals and leading to 774 deaths (3,4). MERS-CoV emerged in 2012 and has so far caused 2,494 infections and 858 deaths (29). More recently, in November/December 2019, a new coronavirus, named SARS-CoV-2, emerged in Hubei province, mainland China, and has been responsible for the “new coronavirus disease” (coronavirus disease 2019, COVID-19) (12,32). At the moment, COVID-19 has assumed a pandemic status (30).
On February 14, 2020, an article by “The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team” opened a horizon for discussions on SARS-CoV-2 and COVID-19 (21). In mainland China, as of February 11, 2020, the highest death rates by COVID-19 occurred in individuals >60 years old and no death was recorded in children <9 years old. In addition, hypertension, diabetes and cardiovascular disease would be risk factors for COVID-19 (21). This epidemiological profile raises several issues that must be discussed, for example: (i) why the highest rates of both critical COVID-19 and death in the elderly?; (ii) why the opposite situation for children?; and (iii) why would hypertension, diabetes and cardiovascular disease be associated with more severe COVID-19?
Antibody-dependent enhancement (ADE) resulting from successive infections by antigenically related viruses has been extensively described and recognized as an important mechanism of viral pathogenesis. In vitro and/or in vivo evidence of ADE has been reported for several viruses, such as human immunodeficiency (11), influenza (28), Ebola (18) and dengue (DENV) viruses (10).
Regarding coronaviruses, several studies have also reported in vitro and/or in vivo ADE for SARS-CoV (16,17,27), MERS-CoV (26) and animal coronaviruses, for example, Feline infectious peritonitis virus (FIPV) (7,14,24). In this regard, an issue is imperative: would it be possible for antibodies induced by previous infections with other human coronaviruses to lead to SARS-CoV-2 ADE? If this possibility is real, ADE may be an additional factor to explain the greater severity of COVID-19 in the elderly, since they probably had more opportunities to be infected by coronaviruses throughout their lives.
Although previous authors have considered some of these aspects (2,23), an issue has not yet been addressed: could maternal antibodies against other human coronaviruses influence the course of SARS-CoV-2 infection in newborn and/or young children? In dengue—an interesting model for ADE studies—maternal anti-DENV antibodies transmitted to fetuses can protect newborns from DENV infections. However, as neutralizing antibody levels decline after the 4th or 6th month of life, ADE outweighs virus neutralization and the infant has an increased risk to develop severe forms of dengue (5). Regarding COVID-19, would it be possible that maternal antibodies for other human coronaviruses, ADE-related (?), and against SARS-CoV-2 (potentially virus neutralizing) have a similar dynamics?
In addition to these issues, it is very important to highlight that in natural infections by human coronaviruses, the participation of cells expressing receptors for the antibody fragment crystallizable (Fc) region is still unclear. Consequently, a possible role of ADE in SARS-CoV-2 infections should be cautiously taken.
Recent studies have also identified the angiotensin converting enzyme 2 (ACE2) as the cell receptor used by SARS-CoV-2; the same receptor identified for SARS-CoV (13,25). Therefore, the hypothesis that cell conditions that increase ACE2 expression would facilitate SARS-CoV-2 infection may be plausible. Cunningly, Fang et al. (9) suggested that “patients with cardiac diseases, hypertension, or diabetes, who are treated with ACE2-increasing drugs, are at higher risk for severe COVID-19.” Indeed, this observation probably helps to explain the high risk of severe COVID-19 in individuals with these morbidities.
Amid the whirlwind of SARS-CoV-2 information, a piece of news released by the media drew attention: individuals previously tested positive for COVID-19 returned to be viral RNA-positive after a period of negative diagnosis. Although these samples need also to be investigated for the presence of infectious viral particles, this finding raised the question of whether these individuals had been reinfected or whether they had intermittent viral shedding.
The possibility that these individuals have been cured and then early reinfected does not seem plausible, at least from the immunological point of view. Previous studies with human and animal coronaviruses report the development of an adaptive immune response postinfection or postimmunization (1,24,31). It is also important to note that the possibility of an early reinfection would reduce the hope of a pandemic decline through massive vaccination.
Regarding intermittent viral shedding, herein it is opportune to make a parallel with animal coronaviruses. Infectious bronchitis virus (IBV), for example, is a highly contagious gammacoronavirus that targets the upper respiratory tract of chickens for primary replication, but then reaches other tissues, leading to a multisystemic infection. Interestingly, IBV has long being recognized as a virus that causes prolonged or intermittent shedding. In these cases, some sites have been proposed for virus persistence, such as kidneys, caecal tonsils and respiratory tract (20,22).
In COVID-19, it should not be disregarded that SARS-CoV-2 could use a similar mechanism of persistence in specific cells/tissues. As the systemic SARS-CoV-2 infection is still uncertain, we suggest starting the investigation of a possible viral persistence in respiratory tract cells. In addition to deepening the knowledge about the virus–host interaction, this information would have important implications on the SARS-CoV-2 containment policy, mainly in relation to the quarantine guidelines.
Finally, although the pathogenesis of COVID-19 is complex and multifactorial, properly addressing the above issues is essential for understanding the pathogenic mechanisms of SARS-CoV-2. We believe that knowledge accumulated on SARS-CoV and MERS-CoV, in addition to studies with animal coronaviruses, is fundamental to direct future investigations, as well as an additional and useful tool for the management of future pandemics.
Footnotes
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this study.