Association of Toll-Like Receptor 7 and 8 Polymorphisms with Covid-19 Severity

Objectives: Toll-like receptors (TLRs) are an important family of receptors that recognize infectious agents and play an important role in the innate immune system. TLRs are a potential candidate to control infection in the early stages of the disease and to produce vaccines against SARS-CoV-2. In addition, studies have suggested that TLR polymorphisms are also associated with antiviral responses against SARS-CoV-2. Therefore, we aimed to investigate the relationship of TLR7 and TLR8 polymorphisms with COVID-19 disease prognosis. Materials-Methods: A total of 120 COVID-19 patients, including 40 outpatients, 40 patients with mild and moderate clinical status, hospitalized and severe pneumonia, and 40 patients followed in the intensive care unit (ICU), were included in the study. The classification of disease severity was made according to WHO criteria. TLR7 (rs179009), TLR8 -129 C/G (rs3764879) and TLR8 Met1Val (rs3764880) polymorphisms were genotyped using the PCR-RFLP method. Result(s): Since TLR7 and TLR8 are located on the X chromosome, men and women were analyzed separately. There was no significant difference between the groups in terms of 3 polymorphisms in males. On the other hand, in women, individuals carrying AG genotype and G allele for TLR8 Met1Val polymorphism were found at a higher rate in patients hospitalized in ICU than in patients followed in the service (p <0.05). In terms of the other two polymorphisms, no significant difference was found between the groups in women. Conclusion(s): We suggest that the AG genotype and G allele of TLR8 Met1Val polymorphism can be considered as an important risk factor that increases the severity of the disease in women.

Epigenetic features, methods, and implementations associated with COVID-19

The infection and life cycle of severe acute respiratory syndrome coronavirus 2 are widely studied, yet multiple gaps exist in the knowledge that affects therapeutic developments against coronavirus disease 2019 (COVID-19). Predominantly caused by a respiratory virus, COVID-19 is not restricted to the respiratory tract but affects multiple organs of the body including the cardiovascular, neurological, immunological, and renal systems. COVID-19 affects all age groups, although the elderly population inherently presenting with multiple comorbidities are disproportionately affected. The majority of the patients experience mild symptoms, although moderate, severe, and critical symptoms occur in a smaller group of patients. Interestingly, the effects of the disease can be acute or chronic and present an ongoing health care challenge. Epigenetic mechanisms of COVID-19 (DNA methylation, histone posttranslational modifications, histone citrullination, etc.) are an emerging field and present enormous potential toward the medical management of COVID-19. Angiotensin converting enzyme 2, an important protein in the cardiovascular system, is a receptor for viral entry into cells, and the epigenetic processes that regulate this protein have been widely studied. Identification of the epitranscriptomic profile has led to the identification of putative biomarkers for disease diagnosis and trials of novel epidrugs for targeted therapy. © 2023 Elsevier Inc. All rights reserved.

Sex chromosome complement and sex steroid signaling underlie sex differences in immunity to respiratory virus infection.

Epidemiological studies have revealed sex differences in the incidence and morbidity of respiratory virus infection in the human population, and often these observations are correlated with sex differences in the quality or magnitude of the immune response. Sex differences in immunity and morbidity also are observed in animal models of respiratory virus infection, suggesting differential dominance of specific immune mechanisms. Emerging research shows intrinsic sex differences in immune cell transcriptomes, epigenomes, and proteomes that may regulate human immunity when challenged by viral infection. Here, we highlight recent research into the role(s) of sex steroids and X chromosome complement in immune cells and describe how these findings provide insight into immunity during respiratory virus infection. We focus on the regulation of innate and adaptive immune cells by receptors for androgen and estrogens, as well as genes with a propensity to escape X chromosome inactivation. A deeper mechanistic knowledge of these pathways will help us to understand the often significant sex differences in immunity to endemic or pandemic respiratory pathogens such as influenza viruses, respiratory syncytial viruses and pathogenic coronaviruses.

Molecular Study of ACE2 Gene Polymorphism of COVID-19 Infection among the Kurdish Population in Kurdistan Region- Iraq.

Coronavirus Disease 2019 (COVID-19) is a current pandemic infection of the human respiratory system, which is caused by which caused by Sever Acute respiratory syndrome virus 2 (SARS-CoV-2). The infection was classified by World Health Organization (WHO) as a universal pandemic in February 2020; there have been 494.587.638 confirmed cases and 6.170.283 deaths. The present study investigated the molecular genetics of the Angiotensin Converting Enzyme 2 (ACE2) gene in correlation to COVID-19 patients in the Kurdish population. Eighty-six individuals were clinically diagnosed with COVID-19 and control groups. After the genomic DNA extraction these participants the target 1, 2 and 8 exons of the ACE2 gene were amplified using the PCR technique, and then the Sanger sequencing technique was performed to analyze genetic variants of the ACE2 gene in 70 DNA samples of COVID-19 hospital patients at Emergency Hospital in Erbil city, Sarchnar Hospital in Sulaymaniyah city, Lalav Hospital in Duhok city and Wafa Hospital in Halabja city from Kurdistan Region of Iraq. The current study was designed into two groups control group and a patient group. The patient group was divided into two subgroups, severe and mild patients of different ages and genders. As a result, there were no mutations at the positions 1, 2 and 8 exons sequences, while single nucleotide polymorphisms (SNPs) were detected and identified three different types of mutation at intron position: twenty-six of c.12405 del T, two of c.12407 T>G, and two of c.12406 G>A in a total 86 participants. This result shows that genetic difference does not impact the COVID-19 infection severity among the Kurdish population regarding ACE2 gene polymorphism.

Unusual X chromosome inactivation maintenance in female alveolar type 2 cells is correlated with increased numbers of X-linked escape genes and sex-biased gene expression.

Sex differences exist for many lung pathologies, including COVID-19 and pulmonary fibrosis, but the mechanistic basis for this remains unclear. Alveolar type 2 cells (AT2s), which play a key role in alveolar lung regeneration, express the X-linked Ace2 gene that has roles in lung repair and SARS-CoV-2 pathogenesis, suggesting that X chromosome inactivation (XCI) in AT2s might impact sex-biased lung pathology. Here we investigate XCI maintenance and sex-specific gene expression profiles using male and female AT2s. Remarkably, the inactive X chromosome (Xi) lacks robust canonical Xist RNA "clouds" and less enrichment of heterochromatic modifications in human and mouse AT2s. We demonstrate that about 68% of expressed X-linked genes in mouse AT2s, including Ace2, escape XCI. There are genome-wide expression differences between male and female AT2s, likely influencing both lung physiology and pathophysiologic responses. These studies support a renewed focus on AT2s as a potential contributor to sex-biased differences in lung disease.

Immunological evaluation of young unvaccinated patients with Turner syndrome after COVID-19.

OBJECTIVES: The X-chromosome contains the largest number of immune-related genes, which play a major role in COVID-19 symptomatology and susceptibility. Here, we had a unique opportunity to investigate, for the first time, COVID-19 outcomes in six unvaccinated young Brazilian patients with Turner syndrome (TS; 45, X0), including one case of critical illness in a child aged 10 years, to evaluate their immune response according to their genetic profile. METHODS: A serological analysis of humoral immune response against SARS-CoV-2, phenotypic characterization of antiviral responses in peripheral blood mononuclear cells after stimuli, and the production of cytotoxic cytokines of T lymphocytes and natural killer cells were performed in blood samples collected from the patients with TS during the convalescence period. Whole exome sequencing was also performed. RESULTS: Our volunteers with TS showed a delayed or insufficient humoral immune response to SARS-CoV-2 (particularly immunoglobulin G) and a decrease in interferon-γ production by cluster of differentiation (CD)4+ and CD8+ T lymphocytes after stimulation with toll-like receptors 7/8 agonists. In contrast, we observed a higher cytotoxic activity in the volunteers with TS than the volunteers without TS after phorbol myristate acetate/ionomycin stimulation, particularly granzyme B and perforin by CD8+ and natural killer cells. Interestingly, two volunteers with TS carry rare genetic variants in genes that regulate type I and III interferon immunity. CONCLUSION: Following previous reports in the literature for other conditions, our data showed that patients with TS may have an impaired immune response against SARS-CoV-2. Furthermore, other medical conditions associated with TS could make them more vulnerable to COVID-19.

Genetic and hormonal mechanisms underlying sex-specific immune responses in tuberculosis.

Tuberculosis (TB), the world's deadliest bacterial infection, afflicts more human males than females, with a male/female (M/F) ratio of 1.7. Sex disparities in TB prevalence, pathophysiology, and clinical manifestations are widely reported, but the underlying biological mechanisms remain largely undefined. This review assesses epidemiological data on sex disparity in TB, as well as possible underlying hormonal and genetic mechanisms that might differentially modulate innate and adaptive immune responses in males and females, leading to sex differences in disease susceptibility. We consider whether this sex disparity can be extended to the efficacy of vaccines and discuss novel animal models which may offer mechanistic insights. A better understanding of the biological factors underpinning sex-related immune responses in TB may enable sex-specific personalized therapies for TB.

Stem cell-derived trophoblast organoids model human placental development, X chromosome inactivation, and susceptibility to emerging pathogens

Problem: Trophoblast organoids derived from human placental villi provide a powerful 3D model system of placental development, but access to first-trimester tissues is limited due to ethical and legal restrictions. Here we sought to establish a methodology for establishing 3D trophoblast organoids from naïve human pluripotent stem cells (hPSCs), which have an expanded potential for extraembryonic differentiation. Method of Study: We previously demonstrated that naïve hPSCs readily give rise to self-renewing human trophoblast cells (hTSCs) that resemble post-implantation cytotrophoblast (CTB) progenitors and can further differentiate into specialized trophoblast lineages. Here we examined whether hTSCs derived from three distinct sources (naïve hPSCs, human blastocysts, and first-trimester placental tissues) have the potential to self-organize into 3D trophoblast organoids by transfer to Matrigel droplets in the presence of trophoblast organoid medium. The expression of protein markers in the resulting stem cellderived trophoblast organoids (SC-TOs) was examined by immunofluorescence and light-sheet microscopy, while their single cell transcriptome was analyzed using the 10X Genomics platform. We also investigated the X chromosome inactivation (XCI) status of organoids derived from female naïve hPSCs and their ability to differentiate into invasive extravillous trophoblast (EVT) organoids. Finally, we evaluated whether SC-TOs are susceptible to infection by various emerging pathogens (SARS-CoV-2 and Zika virus), as a basis for establishing a stem cell-based model system of placental infections during the first trimester. Results: Trophoblast organoids generated from naïve and primary hTSCs displayed comparable tissue architecture, placental hormone secretion, microRNA expression, and capacity for long-term selfrenewal. In-depth single cell transcriptome profiling revealed that SCTOs encompass a variety of trophoblast identities that closely correspond to CTB progenitor, syncytiotrophoblast (STB) and EVT cell types found in human post-implantation embryos. Interestingly, the cellular composition in trophoblast organoids derived from naïve and primary hTSCs was highly similar, which suggests that trophoblast organoid culture represents a powerful attractor state in which the influence of subtle epigenetic differences between naïve and primary hTSCs is mitigated. These organoid cultures displayed clonal XCI patterns previously described in the human placenta.Upon differentiation into specialized EVT organoids, extensive trophoblast invasion was observed in co-culture assays with human endometrial cells. We further demonstrated that SC-TOs display selective vulnerability to infection by SARS-CoV-2 and Zika virus, which correlated with the expression levels of their respective entry factors. Conclusions: The generation of trophoblast organoids from naïve hPSCs provides an accessible and patient-specific 3D model system of the developing placenta and its susceptibility to emerging pathogens. The ability to genetically manipulate naïve hPSCs prior to differentiation into SC-TOs enables functional interrogation of regulatory factors implicated in placental organogenesis.

The first year of a national-access adult Klinefelter's Syndrome multi-disciplinary team (KSMDT) clinic: patient and clinician reported outcomes

Klinefelter's syndrome is the most common chromosomal abnormality seen in men, affecting 1 in 650 men. It is a group of chromosomal disorders with at least one extra X chromosome (47, XXY) occurring due to non-disjunction at the time of gametogenesis. Most adult men are diagnosed at the time of fertility investigations. However, the syndrome has an array of clinical presentations which patients require input from numerous medical specialities during their lifetime. The setting up of a national-access Klinefelter Syndrome multidisciplinary clinic (KSMDT) approach comprising Urology, Endocrinology, Genetics, Reproductive medicine, Radiology, Psychosexual medicine, a specialist pharmacist as well as a patient representative has led to improvements in fertility and long- term management and waiting times. Here we describe the patient-reported outcomes and clinician perspectives of the clinic as it approached its 1st year. Between 2019 and 2020, 72 patients were seen in the adult KS MDT clinic. To assess the quality of care received in the clinic, an 8 -point feedback questionnaire was given to each patient attending the clinic to fill out at the end of the clinic. The form included a space for feedback for each speciality involved. The feedback forms were reviewed by 2 individual researchers and entries were assessed using an adapted Likert scale (0 – 5). Clinicians involved in the clinic were also encouraged to attend and rate the other specialties, the effectiveness of the pre and post clinic MDTs and to describe achievements derived from KSMDT clinic team-working. All the patients (n = 72) took the questionnaire reported that the clinic was beneficial to their understanding of KS & its management and had enough time during consultations. In terms of scoring 86% were very satisfied (score = 5) about genetic consultation compared to 92%, 82%, 82% and 88% in endocrine, fertility, psychosexual and urology consultation, respectively. Key factors influencing these positive results included the presence of an MDT, the access to a patient liaison and knowledge of support groups during the consult, digitized patient information sheets and a cohesive approach between endocrine and fertility teams. Clinician feedback was positive with all members agreeing that the pre and post clinic MDTs allowed effective pinpointing of often missed issues (e.g. hormone induction, social issues). Key milestones for the clinic included the reduction in waiting times by almost 80%, securing funding for costly hormone medication and assisted reproduction, improving sperm retrieval rates (from 11 – 29%) and a thrombo-embolism awareness programme. The overall patient and clinician feedback for the adult KSMDT clinic was uniformly positive, with the multispecialty approach allowing communication with and between all relevant specialities on the same day, avoiding the need to come for multiple separate appointments across different sites (especially relevant during the COVID-19 era). The feedback has also been useful in developing patient information tools such as digital resources and has led to the development of a supportive community group for newly diagnosed KS men. More research is underway to investigate the complex issues affecting KS men long term, after fertility management. Work supported by industry: no. [ FROM AUTHOR] Copyright of Journal of Sexual Medicine is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Unwell Women: Misdiagnosis and Myth in a Man-Made World

It is no laughing matter when endometriosis - a disease that has obviously existed for thousands of years and afflicts 1 in 10 women across the world - is called "a career woman's disease." The history of medicine, of illness, is every bit as social and cultural as it is scientific. - Elinor Cleghorn, in I Unwell Women i I Unwell Women i provides an alternative overview of women's illnesses since the time of Hippocrates. [Extracted from the article] Copyright of American Journal of Clinical Pathology is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Stem-cell-derived trophoblast organoids model human placental development and susceptibility to emerging pathogens.

Trophoblast organoids derived from placental villi provide a 3D model system of human placental development, but access to first-trimester tissues is limited. Here, we report that trophoblast stem cells isolated from naive human pluripotent stem cells (hPSCs) can efficiently self-organize into 3D stem-cell-derived trophoblast organoids (SC-TOs) with a villous architecture similar to primary trophoblast organoids. Single-cell transcriptome analysis reveals the presence of distinct cytotrophoblast and syncytiotrophoblast clusters and a small cluster of extravillous trophoblasts, which closely correspond to trophoblast identities in the post-implantation embryo. These organoid cultures display clonal X chromosome inactivation patterns previously described in the human placenta. We further demonstrate that SC-TOs exhibit selective vulnerability to emerging pathogens (SARS-CoV-2 and Zika virus), which correlates with expression levels of their respective entry factors. The generation of trophoblast organoids from naive hPSCs provides an accessible 3D model system of the developing placenta and its susceptibility to emerging pathogens.

Virtual Screening Attributes Male Biased COVID-19 Mortality to Predicted Antiviral Activity of Female Sex Hormones

Background: Coronavirus disease-19 (COVID-19) is a newly emerged pandemic leading to a state of international alert and leaving millions of infections and thousands of deaths all over the world. Analysis of statistics and epidemiological data for the pandemic outcome pinpointed a puzzling influence of human sex on the heterogeneous outcome of COVID-19, where hospital admissions and mortality were higher among males than females. Two theories explained the observed male-biased COVID-19 mortality based on either dosage of immunoregulatory genes coded in X- chromosomes, or on the abundance of the angiotensin-converting enzyme two (ACE2) receptors in males than females.Objective: In our study, we propose a third scenario through virtual screening of direct antiviral effects of sex hormones.Materials and Methods: Updated screening statistics from 47 countries displaying sex-disaggregated data on COVID-19 were employed and visualized in the form of heatmaps depicting sex difference effects on statistics of cases and deaths. Molecular docking and binding simulations of investigated sex steroids against COVID-19 specific proteins were investigated.Results: Analysis of COVID-19 sex-disaggregated data confirmed that male-biased mortality and computer-aided docking found unexpected female sex hormones biased binding against key targets implicated in the life cycle of COVID-19 compared to the male sex hormone testosterone. Other investigated steroids showed promising docking scores, while the male sex hormone exhibited the lowest affinity.Conclusion: Female sex hormones virtually exhibit direct anti-COVID-19 effect, the proposed antiviral effect of sex hormones should be considered to explain the outcomes of mortality. Moreover, the fluctuation of sex hormones influences sex and personal derived-differential response to COVID-19 infection. © 2021, Bentham Science Publishers. All rights reserved.

Female sex seems to be a favorable factor in COVID-19 era

Coronavirus disease-2019 (COVID-19) is a novel disease that has become a global health problem with high mortality rates. Up to now, there is neither specific treatment nor a vaccine for the disease;hence, the primary goal is to keep patients alive. There is growing evidence that more men than women are dying from the COVID-19. Although the outbreak of COVID-19 has led to the legislation of exceptional public health measures in various countries, fatality difference among genders has not been changed in favor of women. It is important to understand the role of sex to figure out who is most vulnerable to COVID-19 and the risk factors of death. While the precise mechanism of globally observed lower female death rates is still unknown, there are many speculations such as the effect of X chromosome, immunologic distinction, lifestyle choices, and employment status. The aim of this review is to highlight the most relevant connections between COVID-19 and low mortality rate in women globally.

Why Females Do Better: The X Chromosomal TLR7 Gene-Dose Effect in COVID-19.

A male sex bias has emerged in the COVID-19 pandemic, fitting to the sex-biased pattern in other viral infections. Males are 2.84 times more often admitted to the ICU and mortality is 1.39 times higher as a result of COVID-19. Various factors play a role in this, and novel studies suggest that the gene-dose of Toll-Like Receptor (TLR) 7 could contribute to the sex-skewed severity. TLR7 is one of the crucial pattern recognition receptors for SARS-CoV-2 ssRNA and the gene-dose effect is caused by X chromosome inactivation (XCI) escape. Female immune cells with TLR7 XCI escape have biallelic TLR7 expression and produce more type 1 interferon (IFN) upon TLR7 stimulation. In COVID-19, TLR7 in plasmacytoid dendritic cells is one of the pattern recognition receptors responsible for IFN production and a delayed IFN response has been associated with immunopathogenesis and mortality. Here, we provide a hypothesis that females may be protected to some extend against severe COVID-19, due to the biallelic TLR7 expression, allowing them to mount a stronger and more protective IFN response early after infection. Studies exploring COVID-19 treatment via the TLR7-mediated IFN pathway should consider this sex difference. Various factors such as age, sex hormones and escape modulation remain to be investigated concerning the TLR7 gene-dose effect.

Perspectives and Challenges in the Fight Against COVID-19: The Role of Genetic Variability.

In the last year, the advent of the COVID-19 pandemic brought a new consideration for the multidisciplinary sciences. The unknown mechanisms of infection used by SARS-CoV-2 and the absence of effective antiviral pharmacological therapy, diagnosis methods, and vaccines evoked scientific efforts on the COVID-19 outcome. In general, COVID-19 clinical features are a result of local and systemic inflammatory processes that are enhanced by some preexistent comorbidities, such as diabetes, obesity, cardiovascular, and pulmonary diseases, and biological factors, like gender and age. However, the discrepancies in COVID-19 clinical signs observed among those patients lead to investigations about the critical factors that deeply influence disease severity and death. Herein, we present the viral infection mechanisms and its consequences after blocking the angiotensin-converting enzyme 2 (ACE2) axis in different tissues and the progression of inflammatory and immunological reactions, especially the influence of genetic features on those differential clinical responses. Furthermore, we discuss the role of genotype as an essential indicator of COVID-19 susceptibility, considering the expression profiles, polymorphisms, gene identification, and epigenetic modifications of viral entry factors and their recognition, as well as the infection effects on cell signaling molecule expression, which amplifies disease severity.

B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells.

The long non-coding RNA (lncRNA) XIST establishes X chromosome inactivation (XCI) in female cells in early development and thereafter is thought to be largely dispensable. Here, we show XIST is continually required in adult human B cells to silence a subset of X-linked immune genes such as TLR7. XIST-dependent genes lack promoter DNA methylation and require continual XIST-dependent histone deacetylation. XIST RNA-directed proteomics and CRISPRi screen reveal distinctive somatic cell-type-specific XIST complexes and identify TRIM28 that mediates Pol II pausing at promoters of X-linked genes in B cells. Single-cell transcriptome data of female patients with either systemic lupus erythematosus or COVID-19 infection revealed XIST dysregulation, reflected by escape of XIST-dependent genes, in CD11c+ atypical memory B cells (ABCs). XIST inactivation with TLR7 agonism suffices to promote isotype-switched ABCs. These results indicate cell-type-specific diversification and function for lncRNA-protein complexes and suggest expanded roles for XIST in sex-differences in biology and medicine.

Sex Differences in Immunity: Implications for the Development of Novel Vaccines Against Emerging Pathogens.

Vaccines are one of the greatest public health achievements and have saved millions of lives. They represent a key countermeasure to limit epidemics caused by emerging infectious diseases. The Ebola virus disease crisis in West Africa dramatically revealed the need for a rapid and strategic development of vaccines to effectively control outbreaks. Seven years later, in light of the SARS-CoV-2 pandemic, this need has never been as urgent as it is today. Vaccine development and implementation of clinical trials have been greatly accelerated, but still lack strategic design and evaluation. Responses to vaccination can vary widely across individuals based on factors like age, microbiome, co-morbidities and sex. The latter aspect has received more and more attention in recent years and a growing body of data provide evidence that sex-specific effects may lead to different outcomes of vaccine safety and efficacy. As these differences might have a significant impact on the resulting optimal vaccine regimen, sex-based differences should already be considered and investigated in pre-clinical and clinical trials. In this Review, we will highlight the clinical observations of sex-specific differences in response to vaccination, delineate sex differences in immune mechanisms, and will discuss the possible resulting implications for development of vaccine candidates against emerging infections. As multiple vaccine candidates against COVID-19 that target the same antigen are tested, vaccine development may undergo a decisive change, since we now have the opportunity to better understand mechanisms that influence vaccine-induced reactogenicity and effectiveness of different vaccines.

Human genetic factors associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity.

BACKGROUND: The emergence of the novel coronavirus in Wuhan, Hubei Province, China, in December 2019 marked the synchronization of the world to a peculiar clock that is counting infected cases and deaths instead of hours and minutes. The pandemic, highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has indeed caused considerable morbidity and mortality and drastically changed our everyday lives. As we continue to become acquainted with the seventh coronavirus known to infect our species, a number of its characteristics keep surprising us. Among those is the wide spectrum of clinical manifestations of the resulting coronavirus disease 2019 (COVID-19), which ranges from asymptomatic or mildly symptomatic infections to severe pneumonia, respiratory failure, and death. MAIN BODY: Data, now from patient populations, are beginning to accumulate on human genetic factors that may contribute to the observed diversified disease severity. Therefore, we deemed it prudent to review the associations between specific human genetic variants and clinical disease severity or susceptibility to infection that have been reported in the literature to date (at the time of writing this article in early August 2020 with updates in mid-September). With this work, we hope (i) to assist the fast-paced biomedical research efforts to combat the virus by critically summarizing current knowledge on the potential role of host genetics, and (ii) to help guide current genetics and genomics research towards candidate gene variants that warrant further investigation in larger studies. We found that determinants of differing severity of COVID-19 predominantly include components of the immune response to the virus, while determinants of differing susceptibility to SARS-CoV-2 mostly entail genes related to the initial stages of infection (i.e., binding of the cell surface receptor and entry). CONCLUSION: Elucidating the genetic determinants of COVID-19 severity and susceptibility to SARS-CoV-2 infection would allow for the stratification of individuals according to risk so that those at high risk would be prioritized for immunization, for example, if or when safe and effective vaccines are developed. Our enhanced understanding of the underlying biological mechanisms could also guide personalized therapeutics. Such knowledge is already beginning to provide clues that help explain, at least in part, current epidemiologic observations regarding the typically more severe or benign disease course in older males and children, respectively.