LAUSR

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the recent pandemic of coronavirus disease-19 (COVID-19) has a long, positive-sense, non-segmented single-stranded RNA (ssRNA) entrapped by an envelope with spikes. Although SARS-Cov2 infection is largely asymptomatic with people of all age groups and gender are susceptible; the rate of incidence, the severity of the disease and mortality due to COVID-19 vary in different populations. The host genetic make-up has always been suspected to play an important role in almost all infectious diseases and likely to influence the COVID-19 morbidity and mortality as well. The important host genetic factors include genes involved in viral entry into host, pattern recognition receptors (PRRs) and other mediators of innate immunity [1, 2]. Upon successful entry of the virus into human host, while sensing of viral infection and subsequent production of anti-viral immune response (such as production of type I and III interferons) is beneficial, deregulated inflammatory responses with cytokine storms can lead to COVID‐19 immunopathogenesis and disease severity. Most notable amongst the PRRs of the innate immune systems are the toll-like receptors (TLRs) which play crucial role against coronaviruses including COVID-19. Of the 11 different TLRs, structural components of viral envelope are recognised by TLR1, 4 and 6 located on the cell surface with the strongest affinity reported for TLR4 which is activated by oxidised phospholipids produced after SARSCoV2 infection [3, 4]. On the other hand, intracellular TLRs in endosomes such as TLRs7/8 recognise single-stranded positive sense RNA whereas double-stranded RNA intermediate formed during viral replication are sensed by TLR3 [1, 3, 5]. Of these, TLR3 activation is shown to be more effective than TLR4 in mice model [5], and that the role of TLR3 activation is demonstrated to be beneficial against a wide range of RNA virus infections [2, 6, 7]. Interestingly, the high binding affinity of SARS Cov-2 non-structural protein 10 (NSP10) mRNA to TLR3 in docking study suggests a possible induction of TLR3 downstream signalling [3]. Further, protective role of TLR3 has been documented in infections with the more closely related COVID-19 viruses such as SARS-CoV1 and the Middle East respiratory syndrome (MERS-CoV) etc. in previous studies [7, 8]. This insisted us to carry out a genetic association study to examine whether functional genetic variation in the TLR3 gene has a role in the global incidence of COVID-19 across diverse populations. Of the several mutations in TLR3, a non-synonymous mutation in exon 4 (rs3775291) has been shown to impair TLR3 expression and influence subsequent signalling cascade [9]. Further, molecular docking analysis of rs3775291 variant has revealed poor recognition of SARS-CoV-2 dsRNA compared to its wild type variant indicating a possible impaired immune protection [10]. Therefore, we hypothesised that differences in minor allele frequency of rs3775291 across different ethnic populations might have some contributary role in SARS-COV2 susceptibility and mortality. Data on mutant allele frequency from healthy individuals were collected across different population from public-databases for genomic variants (such as 1000 Genomes Project and gnomAD) and literature searches from published articles on PubMed and Google scholars. The COVID-19 related data were acquired from worldometer site (https ://www.world omete rs.info/coron aviru s/) on 18th January, 2020. Data on genotype or allele * Gunanidhi Dhangadamajhi [email protected]