key: cord-254094-ed1epul1
authors: Mayoral, Eduardo Pérez-Campos; Hernández-Huerta, María Teresa; Pérez-Campos Mayoral, Laura; Matias-Cervantes, Carlos Alberto; Mayoral-Andrade, Gabriel; Barrios, Luis Ángel Laguna; Pérez-Campos, Eduardo
title: Factors related to asymptomatic or severe COVID-19 infection
date: 2020-09-24
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.110296
sha: 
doc_id: 254094
cord_uid: ed1epul1

The factors that may contribute to a COVID-19 patient remaining in the asymptomatic stage, or to the infection evolving into the more serious stages are examined. In particular, we refer to the TMPRSS2 expression profile, balance of androgen and estrogen, blood group-A and/or B, nonsynonymous mutations in ORF3, and proteins NS7b and NS8 in SARS-CoV-2. Also, we review other factors related to the susceptibility and pathogenicity of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) has been spreading around the world. As of September 11, 2020, 28,205 ,308 infected subjects and 910,157 deaths have been reported worldwide [1] . Thus, researchers are looking for multiple factors that develop efficient antiviral activity in healthy subjects, resulting in asymptomatic infection. Also, attention must be drawn to the asymptomatic presence of COVID-19 in children, adults and even the elderly. Unlike severe pneumonia with hypercoagulopathy and microvascular immunothrombosis [2] , COVID-19 is more frequent in older subjects and those with comorbidities, however, it is also presented in young people with and without risk factors [3] .

In the first months of the COVID-19 pandemic, most authors focused their attention on features such as the high expression of ACE2 in the salivary glands in asymptomatic infection [4] , and the maturity and binding capacity of ACE2 [5, 6] . Nevertheless, there is a possibility that the presumed asymptomatic stage may depend on the virulence of SARS-CoV-2 and the susceptibility of the subject.

Susceptibility may be related, in part, to the nasopharynx, salivary glands and other tissues. Other factors may also be involved, such as the ACE2 gene polymorphisms, which cause variations in the affinity, binding and processing of the SARS-CoV-2 spike protein [7] , and lower levels of ACE-2 and its posterior angiotensin II up-regulation [8] . Moreover, the TMPRSS2 variation can influence susceptibility [9] because both are expressed in the salivary glands [10] . Other genes involved in the different responses between the sexes to SARS-CoV-2 are SRY, SOX9 and the TMPRSS2 gene [11, 12] . Based on the balance of androgen and estrogen, a low prenatal testosterone/high prenatal estrogen level is indicated by a high mean 2D:4D. This is expressed in females in the index finger (2D), which is generally equal to or longer than the ring finger (4D), while in males, the 2D is usually shorter than the 4D [13] . A higher 2D:4D ratio is associated with COVID-19 severity in men [14] , this means that sex hormones play a role in protection, thus, causing women to develop less serious complications or an asymptomatic COVID-19 Infection [12] .

Following SARS-CoV-2 translation and RNA replication, a complex group of glycans is expressed and added to new viruses [15] . These glycans are formed in cells that co-express ACE2 [16] . Among these new virus glycans, the ABO (H), blood group-A and/or B-specific mucin-types [17] may play an important role, i.e., if the subject is blood group "O" and has anti-A and anti-B antibodies, these antibodies may block the attachment and entry of the virus, similar to SARS-CoV spike protein [18] . This could mean that individuals with blood group O would have a much lower risk of becoming infected, depending on the type of anti-αGal, anti-A or, Anti-B antibodies, as reported in an earlier study [19] . Although there are still no complete studies related to histo-blood group antigens and susceptibility of low or non-secreting fucosyltransferase 2 salivary status, fucosyltransferase 2 is known to be related to viral infections or complications [20] .

Alleles of the major histocompatibility complex (MHC) class I may cause vulnerability to a more severe infection, such as HLA-B*46:01 and, subsequently, to COVID-19, although, HLA-B*15:03 may present a better response of T lymphocytes [21] . Furthermore, a mineralocorticoid receptor that controls blood pressure may explain cardiac injury in severe cases of COVID-19, due to an aberrant CD8+ T cell activation [22] .

A case report based on viral kinetics monitoring, shows that clinical evolution could depend on the viral load in the nasopharynx, despite its limitations due to the number of cases studied [23, 24] .

On the other hand, the 15-30-bp deletions in the S1/S2 cleavage site region attenuate the ability to cause severe lung disease, as seen in the hamster model [25] . Nonsynonymous mutations in ORF3a could be related to the pathogenicity of SARS-CoV-2 [26] . In addition, the mutation of an aspartate (D) at position 614 in the D614G viral spike has a significant correlation with case fatality rates [27] . Thus, the deletion of the accessory proteins in NS7b and NS8 could be related to the virus infectivity [28] . Other important factors considered useful in keeping a subject at the asymptomatic stage are vitamin D levels in addition to 'essential' amino acids (I, L, K, M, F, T, W, V, H) [29] , zinc, and vitamin E status [30] .

The world faces a new disease, named COVID-19 [31] . It begins with a lung infection, which we now know is a significant basis in endothelial inflammation and micro thrombosis [32] . It affects numerous systems and organs such as the cardiovascular, central and peripheral nervous, gastrointestinal, reproductive, and vascular, as well as the haematological, renal, and skin [33] . The elderly are known to have a higher death rate from COVID-19, moreover, more than 30% of infected subjects have comorbidity, men having a 1.5 times greater probability of dying [34] .

The ACE2 receptor and the TMPRSS2 protease facilitate entry of SARS-CoV-2 are highly expressed in the nasal goblet and ciliated cells [35] . The coexpression of these receptors in these cells suggests that they could be the sites of the original infection and possible reservoirs of dissemination [35] . The coexpression of both cells in specific tissues may explain different phenotypes such as gastrointestinal [36] , neurological [37] , cutaneous [38] and ocular [39] , among others.

Mechanistically, it is possible that the interaction of factors related to susceptibility or pathogenicity makes a subject asymptomatic or not. An in-depth study of the factors associated with asymptomatic subjects can provide information to limit severe COVID-19 as much as possible. The evidence reported to date is shown in Table 1 . 

Global initiative on sharing all influenza data -from vision to reality

Hyperinflammation and derangement of reninangiotensin-aldosterone system in COVID-19: A novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis

Predictive factors of severe coronavirus disease 2019 in previously healthy young adults: a single-center, retrospective study

Asymptomatic Infection

A Systematic Review of Asymptomatic Infections with COVID-19

Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19

Sanchis-Gomar F. Do genetic polymorphisms in angiotensin converting enzyme 2 (ACE2) gene play a role in coronavirus disease 2019 (COVID-19)?

The Dilemma of Coronavirus Disease 2019, Aging, and Cardiovascular Disease: Insights From Cardiovascular Aging Science

First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations

Systematic analysis of ACE2 and TMPRSS2 expression in salivary glands reveals underlying transmission mechanism caused by SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated

Sex-Related Differences

Developmental basis of sexually dimorphic digit ratios

Understanding COVID-19: Digit ratio (2D:4D) and sex differences in national case fatality rates

Site-specific glycan analysis of the SARS-CoV-2 spike

Harnessing the natural anti-glycan immune response to limit the transmission of enveloped viruses such as SARS-CoV-2

How Blood Group A Might Be a Risk and Blood Group O Be Protected from SARS-CoV-2 (COVID-19) Infections (How the Virus Invades the Human Body via ABO(H) Blood Group Carbohydrates)

Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies

Relationship between the ABO Blood Group and the COVID-19 Susceptibility

Fucosyltransferase 2 non-secretor and low secretor status predicts severe outcomes in premature infants

Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2

Is aberrant CD8+ T cell activation by hypertension associated with cardiac injury in severe cases of COVID-19?

Clinical and virological data of the first cases of COVID-19 in Europe: a case series

Understanding COVID-19: what does viral RNA load really mean?

Attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction

SARS-CoV-2 and ORF3a: Nonsynonymous Mutations, Functional Domains, and Viral Pathogenesis

SARS-CoV-2 viral spike G614 mutation exhibits higher case fatality rate

Nonstructural proteins NS7b and NS8 are likely to be phylogenetically associated with evolution of 2019-nCoV

Amino acid catabolism: a pivotal regulator of innate and adaptive immunity

Nutritional modulation of age-related changes in the immune system and risk of infection

COVID-19 and the creation of a new disease

The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications

Extrapulmonary manifestations of COVID-19: Radiologic and clinical overview

Immune-epidemiological parameters of the novel coronavirus -a perspective

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

Microthrombosis Associated with Gastrointestinal Bleeding in COVID-19

Neurological associations of COVID-19

Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases

Ocular manifestations and clinical characteristics of 535 cases of COVID-19 in Wuhan, China: a cross-sectional study

ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy

Relationship between ABO blood group distribution and clinical characteristics in patients with COVID-19

25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2

The authors thank Charlotte Grundy and Eli Cruz Parada for their assistance. We also thank the National Technology of Mexico (TecNM) project 8703.20-P.

The authors declare that we have no conflicts of interest.
