VIRAL IMMUNOLOGY
Volume 00, Number 00, 2020
ª Mary Ann Liebert, Inc.
Pp. 1–3
DOI: 10.1089/vim.2020.0059
Issues on Coronavirus Disease 2019
(COVID-19) Pathogenesis
José Valter Joaquim Silva Júnior,1–3 Thaı́sa Regina Rocha Lopes,1
Pablo Sebastian Britto de Oliveira,3 Rudi Weiblen,3 and Eduardo Furtado Flores3
To the Editor:
C oronaviruses belong to the realm Riboviria, order
Nidovirales and family Coronaviridae, which have
two subfamilies, Letovirinae and Orthocoronavirinae. The
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subfamily Orthocoronavirinae comprises four genera,
Alphacoronavirus, Betacoronavirus, Gammacoronavirus
and Deltacoronavirus (15). Among these, only the alpha-
and betacoronaviruses are known to infect humans. To
date, seven human coronaviruses have been identified: HCoV-
229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV
(Severe acute respiratory syndrome-related coronavirus),
MERS-CoV (Middle East respiratory syndrome-related cor-
onavirus) and SARS-CoV-2 (Severe acute respiratory
syndrome-related coronavirus 2) (6). HCoV-229E, HCoV-
NL63 (both alphacoronaviruses), HCoV-OC43 and HCoV-
HKU1 (both betacoronaviruses) are often related to mild
diseases, but may also lead to clinical complications in
specific populations, for example, young, elderly and im-
munocompromised individuals. Infections with SARS-
CoV, MERS-CoV and SARS-CoV-2 (betacoronaviruses),
in turn, are strongly associated with severe respiratory dis-
eases (6,19,32).
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 prov-
ince, 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 Cor-
onavirus 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
1
Virology Sector, Laboratory of Immunopathology Keizo Asami, Federal University of Pernambuco, Pernambuco, Brazil.
2
Department of Microbiology and Parasitology, Federal University of Santa Maria, Santa Maria, Brazil.
3
Virology Sector, Department of Preventive Veterinary Medicine, Federal University of Santa Maria, Santa Maria, Brazil.
1
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 anti-
bodies induced by previous infections with other human
coronaviruses to lead to SARS-CoV-2 ADE? If this possi-
bility 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 cor-
onaviruses 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 in-
fluence 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 possi-
ble 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
 2 LETTER TO THE EDITOR
participation of cells expressing receptors for the antibody
fragment crystallizable (Fc) region is still unclear. Conse-
quently, a possible role of ADE in SARS-CoV-2 infections
should be cautiously taken.
Recent studies have also identified the angiotensin con-
verting 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) sug-
gested 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
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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 post-
immunization (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 oppor-
tune 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 tis-
sues, 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 ton-
sils 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 infec-
tion 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 impli-
cations on the SARS-CoV-2 containment policy, mainly in
relation to the quarantine guidelines.
Finally, although the pathogenesis of COVID-19 is com-
plex 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 in-
vestigations, as well as an additional and useful tool for the
management of future pandemics.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this study.
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Address correspondence to:
Dr. José Valter Joaquim Silva Júnior
Virology Sector
Department of Preventive Veterinary Medicine
Federal University of Santa Maria
Av. Roraima, 1000, Camobi
Santa Maria, Rio Grande do Sul 97105-900
Brazil
E-mail: josevalterjsilvajr@gmail.com
Dr. Eduardo Furtado Flores
Virology Sector
Department of Preventive Veterinary Medicine
Federal University of Santa Maria
Av. Roraima, 1000, Camobi
Santa Maria, Rio Grande do Sul 97105-900
Brazil
E-mail: eduardofurtadoflores@gmail.com