Genetic, Clinical, Epidemiological, and Immunological Profiling of IgG Response Duration after SARS-CoV-2 Infection.

The IgG response against SARS-CoV-2 infection can persist for over six months (long response; LR). However, among 30% of those infected, the duration can be as short as three months or less (short response; SR). The present study assembled serological data on the anti-SARS-CoV-2 IgG response duration of two previous studies and integrated these results with the plasmatic cytokine levels and genetic profile of 10 immune-relevant SNPs that were also previously published, along with the plasmatic total IgG, IgA, and IgM levels, allowing for the genetic, clinical, immunological, and epidemiological aspects of the post-COVID-19 IgG response duration to be understood. The SR was associated with previous mild acute COVID-19 and with an SNP (rs2228145) in IL6R related to low gene expression. Additionally, among the SR subgroup, no statistically significant Spearman correlations were observed between the plasma levels of IL-17A and the Th17 regulatory cytokines IFN-γ (rs = 0.2399; p = 0.1043), IL-4 (rs = 0.0273; p = 0.8554), and IL-2 (rs = 0.2204; p = 0.1365), while among the LR subgroup, weaker but statistically significant Spearman correlations were observed between the plasma levels of IL-17A and IFN-γ (rs = 0.3873; p = 0.0016), IL-4 (rs = 0.2671; p = 0.0328), and IL-2 (rs = 0.3959; p = 0.0012). These results suggest that the Th17 response mediated by the IL-6 pathway has a role in the prolonged IgG response to SARS-CoV-2 infection.

NGF (-198C > T, Ala35Val) and p75NTR (Ser205Leu) gene mutations are associated with liver function in different histopathological profiles of the patients with chronic viral hepatitis in the Brazilian Amazon.

BACKGROUNDS: Neural growth factor (NGF) is a neurotrophin that can interact with the p75NTR receptor and initiate a cascade of reactions that determines cell survival or death, and both are associated with the physiology of liver tissue. Single nucleotide polymorphisms (SNPs) in the NGF and p75NTR genes have been investigated in different pathologies; however, there are no studies that have analyzed their biological roles in the hepatic microenvironment. In the present study, we evaluated the impact of SNPs in these genes on the maintenance of liver function at different stages of inflammation and fibrosis in patients with chronic viral liver disease in the Brazilian Amazon. METHODS: The SNPs -198C > T, Arg80Gln, Val72Met, Ala35Val, Ala18Ala and Ser205Leu were genotyped by real-time PCR in samples from patients with chronic viral hepatitis stratified by stage of inflammation and liver fibrosis. Histopathological, viral load (VL), liver enzyme and comorbidities data were obtained from updated medical records. Other aspects were highlighted by applied epidemiological questionnaires. RESULTS: The -198C/T and Ala35Val polymorphisms in NGF were associated with changes in histopathological profiles, VL and liver enzymes. Ser205Leu polymorphism in p75NTR was associated only with changes in VL and liver enzymes. Polymorphic frequencies were variable among different ethnic populations, mainly for biologically relevant polymorphisms. A multifactorial network of interactions has been established based on genetic, virological, behavioral and biochemical aspects. CONCLUSION: Mutations in the NGF (-198C > T, Ala35Val) and p75NTR (Ser205Leu) genes, within the list of multifactorial aspects, are associated with liver function in different histopathological profiles of patients with chronic viral liver disease in the Brazilian Amazon.

The Silent Syndrome of Long COVID and Gaps in Scientific Knowledge: A Narrative Review.

COVID-19 is still a major public health concern, mainly due to the persistence of symptoms or the appearance of new symptoms. To date, more than 200 symptoms of long COVID (LC) have been described. The present review describes and maps its relevant clinical characteristics, pathophysiology, epidemiology, and genetic and nongenetic risk factors. Given the currently available evidence on LC, we demonstrate that there are still gaps and controversies in the diagnosis, pathophysiology, epidemiology, and detection of prognostic and predictive factors, as well as the role of the viral strain and vaccination.

Association of the IFNG +874T/A Polymorphism with Symptomatic COVID-19 Susceptibility.

Tumor necrosis factor (TNF) and interferon-gamma (IFNγ) are important inflammatory mediators in the development of cytokine storm syndrome (CSS). Single nucleotide polymorphisms (SNPs) regulate the expression of these cytokines, making host genetics a key factor in the prognosis of COVID-19. In this study, we investigated the associations of the TNF -308G/A and IFNG +874T/A polymorphisms with COVID-19. We analyzed the frequencies of the two polymorphisms in the control groups (CG: TNF -308G/A, n = 497; IFNG +874T/A, n = 397), a group of patients with COVID-19 (CoV, n = 222) and among the subgroups of patients with nonsevere (n = 150) and severe (n = 72) COVID-19. We found no significant difference between the genotypic and allelic frequencies of TNF -308G/A in the groups analyzed; however, both the frequencies of the high expression genotype (TT) (CoV: 13.51% vs. CG: 6.30%; p = 0.003) and the *T allele (CoV: 33.56% vs. CG: 24. 81%; p = 0.001) of the IFNG +874T/A polymorphism were higher in the COVID-19 group than in the control group, with no differences between the subgroups of patients with nonsevere and severe COVID-19. The *T allele of IFNG +874T/A (rs2430561) is associated with susceptibility to symptomatic COVID-19. These SNPs provided valuables clues about the potential mechanism involved in the susceptibility to developing symptomatic COVID-19.

Severe COVID-19 and long COVID are associated with high expression of STING, cGAS and IFN-α.

The cGAS-STING pathway appears to contribute to dysregulated inflammation during coronavirus disease 2019 (COVID-19); however, inflammatory factors related to long COVID are still being investigated. In the present study, we evaluated the association of cGAS and STING gene expression levels and plasma IFN-α, TNF-α and IL-6 levels with COVID-19 severity in acute infection and long COVID, based on analysis of blood samples from 148 individuals, 87 with acute COVID-19 and 61 in the post-COVID-19 period. Quantification of gene expression was performed by real-time PCR, and cytokine levels were quantified by ELISA and flow cytometry. In acute COVID-19, cGAS, STING, IFN-α, TNF-α, and IL-6 levels were higher in patients with severe disease than in those with nonsevere manifestations (p < 0.05). Long COVID was associated with elevated cGAS, STING and IFN-α levels (p < 0.05). Activation of the cGAS-STING pathway may contribute to an intense systemic inflammatory state in severe COVID-19 and, after infection resolution, induce an autoinflammatory disease in some tissues, resulting in long COVID.

Association of killer cell immunoglobulin-like receptor polymorphisms with chronic hepatitis C and responses to therapy in Brazil.

Soroprevalence for Hepatitis C virus is reported as 2.12% in Northern Brazil, with about 50% of the patients exhibiting a sustained virological response (SVR). Aiming to associate polymorphisms in Killer Cell Immunoglobulin-like Receptors (KIR) with chronic hepatitis C and therapy responses we investigated 125 chronic patients and 345 controls. Additionally, 48 ancestry markers were genotyped to control for population stratification. The frequency of the KIR2DL2 and KIR2DL2+HLA-C(Asp80) gene and ligand was higher in chronic infected patients than in controls (p < 0.0009, OR = 3.4; p = 0.001, OR = 3.45). In fact, KIR2DL3 is a weaker inhibitor of NK activity than KIR2DL2, which could explain the association of KIR2DL2 with chronic infection. Moreover, KIR2DS2 and KIR2DS2+HLA-C(Asp80) (p < 0.0001, OR = 2.51; p = 0.0084, OR = 2.62) and KIR2DS3 (p < 0.0001; OR = 2.57) were associated with chronic infection, independently from KIR2DL2. No differences in ancestry composition were observed between control and patients, even with respect to therapy response groups. The allelic profile KIR2DL2/KIR2DS2/KIR2DS3 was associated with the chronic hepatitis C (p < 0.0001; OR = 3). Furthermore, the patients also showed a higher mean number of activating genes and a lower frequency of the homozygous AA profile, which is likely secondary to the association with non-AA and/or activating genes. In addition, the KIR2DS5 allele was associated with SVR (p = 0.0261; OR = 0.184).The ancestry analysis of samples ruled out any effects of population substructuring and did not evidence interethnic differences in therapy response, as suggested in previous studies.

Imbalance of Peripheral Temperature, Sympathovagal, and Cytokine Profile in Long COVID.

A persistent state of inflammation has been reported during the COVID-19 pandemic. This study aimed to assess short-term heart rate variability (HRV), peripheral body temperature, and serum cytokine levels in patients with long COVID. We evaluated 202 patients with long COVID symptoms categorized them according to the duration of their COVID symptoms (≤120 days, n = 81; >120 days, n = 121), in addition to 95 healthy individuals selected as controls. All HRV variables differed significantly between the control group and patients with long COVID in the ≤120 days group (p < 0.05), and participants in the long COVID ≤120 days group had higher temperatures than those in the long COVID >120 days group in all regions analysed (p < 0.05). Cytokine analysis showed higher levels of interleukin 17 (IL-17) and interleukin 2 (IL-2), and lower levels of interleukin 4 (IL-4) (p < 0.05). Our results suggest a reduction in parasympathetic activation during long COVID and an increase in body temperature due to possible endothelial damage caused by the maintenance of elevated levels of inflammatory mediators. Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 appear to constitute a long-term profile of COVID-19 cytokines, and these markers are potential targets for long COVID-treatment and prevention strategies.

Thrombophilia and Immune-Related Genetic Markers in Long COVID.

Aiming to evaluate the role of ten functional polymorphisms in long COVID, involved in major inflammatory, immune response and thrombophilia pathways, a cross-sectional sample composed of 199 long COVID (LC) patients and a cohort composed of 79 COVID-19 patients whose follow-up by over six months did not reveal any evidence of long COVID (NLC) were investigated to detect genetic susceptibility to long COVID. Ten functional polymorphisms located in thrombophilia-related and immune response genes were genotyped by real time PCR. In terms of clinical outcomes, LC patients presented higher prevalence of heart disease as preexistent comorbidity. In general, the proportions of symptoms in acute phase of the disease were higher among LC patients. The genotype AA of the interferon gamma (IFNG) gene was observed in higher frequency among LC patients (60%; p = 0.033). Moreover, the genotype CC of the methylenetetrahydrofolate reductase (MTHFR) gene was also more frequent among LC patients (49%; p = 0.045). Additionally, the frequencies of LC symptoms were higher among carriers of IFNG genotypes AA than among non-AA genotypes (Z = 5.08; p < 0.0001). Two polymorphisms were associated with LC in both inflammatory and thrombophilia pathways, thus reinforcing their role in LC. The higher frequencies of acute phase symptoms among LC and higher frequency of underlying comorbidities might suggest that acute disease severity and the triggering of preexisting condition may play a role in LC development.

Antibody Response to the SARS-CoV-2 Spike and Nucleocapsid Proteins in Patients with Different COVID-19 Clinical Profiles.

The first case of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in Brazil was diagnosed on February 26, 2020. Due to the important epidemiological impact of COVID-19, the present study aimed to analyze the specificity of IgG antibody responses to the S1, S2 and N proteins of SARS-CoV-2 in different COVID-19 clinical profiles. This study enrolled 136 individuals who were diagnosed with or without COVID-19 based on clinical findings and laboratory results and classified as asymptomatic or as having mild, moderate or severe disease. Data collection was performed through a semistructured questionnaire to obtain demographic information and main clinical manifestations. IgG antibody responses to the S1 and S2 subunits of the spike (S) protein and the nucleocapsid (N) protein were evaluated using an enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions. The results showed that among the participants, 87.5% (119/136) exhibited IgG responses to the S1 subunit and 88.25% (120/136) to N. Conversely, only 14.44% of the subjects (21/136) displayed S2 subunit responses. When analyzing the IgG antibody response while considering the different proteins of the virus, patients with severe disease had significantly higher antibody responses to N and S1 than asymptomatic individuals (p ≤ 0.0001), whereas most of the participants had low antibody titers against the S2 subunit. In addition, individuals with long COVID-19 showed a greater IgG response profile than those with symptomatology of a short duration. Based on the results of this study, it is concluded that levels of IgG antibodies may be related to the clinical evolution of COVID-19, with high levels of IgG antibodies against S1 and N in severe cases and in individuals with long COVID-19.

Polymorphisms in the MBL2 gene are associated with the plasma levels of MBL and the cytokines IL-6 and TNF-α in severe COVID-19.

Introduction: Mannose-binding lectin (MBL) promotes opsonization, favoring phagocytosis and activation of the complement system in response to different microorganisms, and may influence the synthesis of inflammatory cytokines. This study investigated the association of MBL2 gene polymorphisms with the plasma levels of MBL and inflammatory cytokines in COVID-19. Methods: Blood samples from 385 individuals (208 with acute COVID-19 and 117 post-COVID-19) were subjected to real-time PCR genotyping. Plasma measurements of MBL and cytokines were performed by enzyme-linked immunosorbent assay and flow cytometry, respectively. Results: The frequencies of the polymorphic MBL2 genotype (OO) and allele (O) were higher in patients with severe COVID-19 (p< 0.05). The polymorphic genotypes (AO and OO) were associated with lower MBL levels (p< 0.05). IL-6 and TNF-α were higher in patients with low MBL and severe COVID-19 (p< 0.05). No association of polymorphisms, MBL levels, or cytokine levels with long COVID was observed. Discussion: The results suggest that, besides MBL2 polymorphisms promoting a reduction in MBL levels and therefore in its function, they may also contribute to the development of a more intense inflammatory process responsible for the severity of COVID-19.

Association of Polymorphisms of IL-6 Pathway Genes (IL6, IL6R and IL6ST) with COVID-19 Severity in an Amazonian Population.

Interleukin-6 has been recognized as a major role player in COVID-19 severity, being an important regulator of the cytokine storm. Hence, the evaluation of the influence of polymorphisms in key genes of the IL-6 pathway, namely IL6, IL6R, and IL6ST, may provide valuable prognostic/predictive markers for COVID-19. The present cross-sectional study genotyped three SNPs (rs1800795, rs2228145, and rs7730934) at IL6. IL6R and IL6ST genes, respectively, in 227 COVID-19 patients (132 hospitalized and 95 non-hospitalized). Genotype frequencies were compared between these groups. As a control group, published data on gene and genotype frequencies were gathered from published studies before the pandemic started. Our major results point to an association of the IL6 C allele with COVID-19 severity. Moreover, IL-6 plasmatic levels were higher among IL6 CC genotype carriers. Additionally, the frequency of symptoms was higher at IL6 CC and IL6R CC genotypes. In conclusion, the data suggest an important role of IL6 C allele and IL6R CC genotype on COVID-19 severity, in agreement with indirect evidence from the literature about the association of these genotypes with mortality rates, pneumonia, and heightening of protein plasmatic levels pro-inflammatory driven effects.

ß-Globin polymorphisms in Amerindian populations from the Brazilian Amazon.

OBJECTIVES: This investigation was performed to examine genetic variation at the ß-globin locus in a sample of 30 healthy individuals from native populations in South America. The patterns of haplotypic variation were compared with those of previous studies including samples for various worldwide populations in an attempt to make inferences about the occupation of the Americas from a deeper temporal perspective than is typically available with haploid markers. METHODS: A 2.67-kb segment containing the ß-globin gene and its flanking regions was examined for genetic variation in a sample of 60 chromosomes from native populations in South America. The fragment was PCR-amplified and directly sequenced. To determine linkage relationships in compound heterozygotes, we used the amplification refractory mutation system. In addition, we assessed genetic variability and differentiation among populations, and we performed tests of selective neutrality. These analyses were performed for Brazilian Amerindian group and other worldwide populations previously studied. RESULTS: Eleven polymorphic sites were found in the studied fragment, which distinguished eight different haplotypes, three recombinants haplotypes (present as single copies) and five previously described haplotypes, including some of those most highly differentiated. Genetic variation found in the pooled sample is substantial. CONCLUSIONS: Although only five known haplotypes are observed in Amazonia, some of these are highly divergent, resulting in patterns of molecular polymorphism equal to or higher than those from other world regions.

Artificial blood-feeding of phlebotomines (Diptera: Psychodidae: Phlebotominae): is it time to repurpose biological membranes in light of ethical concerns?

BACKGROUND: The aims of the present study were to evaluate and compare the efficacy of blood-feeding in phlebotomines through industrially processed membranes from the small intestine of pigs (used for the production of commercial sausages) and the skin of euthanized chicks. METHODS: Laboratory-bred Lutzomyia longipalpis and different field-caught phlebotomine species were subjected to the artificial feeding systems under similar conditions. Paired tests were performed using the control (skin from euthanized chicks) and test membranes (pig small intestine). The feeding rates were compared by paired t-test, and Pearson correlation was used to examine the relationship between the thickness of the membranes and feeding rate. RESULTS: The feeding rate was greater with the test membrane than with the control membrane for L. longipalpis (t-test, t = -3.3860, P = 0.0054) but not for the most frequent field-caught species, Nyssomyia antunesi (t-test, t = 0.7746, P = 0.4535). The average thicknesses of the control and test membranes were 184 ± 83 µm and 34 ± 12 µm, respectively (Mann-Whitney U-test, U = 0.00, Z = 2.8823, P = 0.0039); however, there was no correlation between feeding rate and membrane thickness. A moderate positive correlation was observed between the number of phlebotomines that fed and the total number of phlebotomines in the cage for each type of membrane and for each species. CONCLUSIONS: The test membrane is a viable alternative for the artificial blood-feeding of phlebotomines, and is thus a potential substitute for the skin of animals that are euthanized for this purpose. Feeding rate was independent of membrane thickness.

The Complexity of SARS-CoV-2 Infection and the COVID-19 Pandemic.

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the death of millions of people worldwide and thousands more infected individuals developed sequelae due to the disease of the new coronavirus of 2019 (COVID-19). The development of several studies has contributed to the knowledge about the evolution of SARS-CoV2 infection and the disease to more severe forms. Despite this information being debated in the scientific literature, many mechanisms still need to be better understood in order to control the spread of the virus and treat clinical cases of COVID-19. In this article, we carried out an extensive literature review in order to bring together, in a single article, the biological, social, genetic, diagnostic, therapeutic, immunization, and even socioeconomic aspects that impact the SAR-CoV-2 pandemic. This information gathered in this article will enable a broad and consistent reading of the main aspects related to the current pandemic.

Phylogeny of Anopheles darlingi (Diptera:Culicidae) based on the antimicrobial peptide genes cecropin and defensin.

Cecropins and defensins are the main classes of antimicrobial peptides in the mosquito innate immune system, acting against bacteria, fungi and protozoa. There is a knowledge gap concerning these peptide genes in anopheline mosquitoes from the Brazilian Amazon. Thus, this work aimed to describe molecular techniques for detecting the genes encoding the antimicrobial peptides cecropin A (CecA) and defensin in Anopheles darlingi mosquitoes and to perform molecular phylogeny of the sequenced genes using the maximum likelihood method and Bayesian inference with other species from different geographic areas. Our results show, for the first time, a molecular biology method for detecting CecA and defensin in Anopheles darlingi that allows for the use of these molecular markers for phylogenetic analysis in anopheline species, separating the species into single and monophyletic clades.

Prevalence and Risk Factors for HTLV-1/2 Infection in Quilombo Remnant Communities Living in the Brazilian Amazon.

Human T-lymphotropic viruses 1 and 2 (HTLV-1 and HTLV-2) are retroviruses that originated on the African continent and dispersed throughout other continents through human migratory flows. This study describes the prevalence of HTLV-1 and HTLV-2 infection in residents of 11 quilombo remnant communities in the state of Pará, Brazil, and the associated risk factors. A total of 859 individuals (334 men and 525 women), aged between 7 and 91 years, participated in the study. All subjects answered a questionnaire with questions on sociodemographic characteristics and on risk factors associated with HTLV infection, and blood samples were collected and separated into plasma and leukocytes. An immunoenzymatic assay (ELISA; Murex HTLV-I+II, DiaSorin, Dartford, UK) was used as a screening test, and positive samples were subjected to line immunoassay confirmatory tests (Inno-LIA HTLV I/II Score FUJIREBIO) and DNA extraction for subsequent real-time PCR to differentiate the viral type. Four of the 859 individuals were seropositive for HTLV. HTLV-1 infection was confirmed in one individual from the Itamoari community (0.92%), and HTLV-2 infection was confirmed in two individuals from São Benedito (3.17%) and in one individual from Arimandeua (2.22%). Blood transfusion was the only risk factor associated with HTLV infection in this study. This study reports the occurrence of HTLV-1 and HTLV-2 in quilombo remnant communities in the state of Pará. Considering the African origin of the virus and its introduction into Brazil from the slave trade, the continued evaluation of quilombola communities in the state of Pará is essential to better characterize the distribution of infections in these populations and to create public health policies for the control of the spread of the virus and associated diseases.

HLA-B*13, B*35 and B*39 Alleles Are Closely Associated With the Lack of Response to ART in HIV Infection: A Cohort Study in a Population of Northern Brazil.

Introduction: Immune reconstitution failure after HIV treatment is a multifactorial phenomenon that may also be associated with a single polymorphism of human leukocyte antigen (HLA); however, few reports include patients from the Brazilian Amazon. Our objective was to evaluate the association of the immunogenic profile of the "classical" HLA-I and HLA-II loci with treatment nonresponse in a regional cohort monitored over 24 months since HIV diagnosis. Materials and Methods: Treatment-free participants from reference centers in the state of Pará, Brazil, were enrolled. Infection screening was performed using enzyme immunoassays (Murex AG/AB Combination DiaSorin, UK) and confirmed by immunoblots (Bio-Manguinhos, FIOCRUZ). Plasma viral load was quantified by real-time PCR (ABBOTT, Chicago, Illinois, USA). CD4+/CD8+ T lymphocyte quantification was performed by immunophenotyping and flow cytometry (BD Biosciences, San Jose, CA, USA). Infection was monitored via test and logistics platforms (SISCEL and SICLOM). Therapeutic response failure was inferred based on CD4+ T lymphocyte quantification after 1 year of therapy. Loci A, B and DRB1 were genotyped using PCR-SSO (One Lambda Inc., Canoga Park, CA, USA). Statistical tests were applied using GENEPOP, GraphPad Prism 8.4.3 and BioEstat 5.3. Results: Of the 270 patients monitored, 134 responded to treatment (CD4+ ≥ 500 cells/µL), and 136 did not respond to treatment (CD4+ < 500 cells/µL). The allele frequencies of the loci were similar to heterogeneous populations. The allelic profile of locus B was statistically associated with treatment nonresponse, and the B*13, B*35 and B*39 alleles had the greatest probabilistic influence. The B*13 allele had the highest risk of treatment nonresponse, and carriers of the allele had a detectable viral load and a CD4+ T lymphocyte count less than 400 cells/µL with up to 2 years of therapy. The B*13 allele was associated with a switch in treatment regimens, preferably to efavirenz (EFZ)-based regimens, and among those who switched regimens, half had a history of coinfection with tuberculosis. Conclusions: The allelic variants of the B locus are more associated with non-response to therapy in people living with HIV (PLHIV) from a heterogeneous population in the Brazilian Amazon.

Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome.

The duration and severity of COVID-19 are related to age, comorbidities, and cytokine synthesis. This study evaluated the impact of these factors on patients with clinical presentations of COVID-19 in a Brazilian cohort. A total of 317 patients diagnosed with COVID-19 were included; cases were distributed according to clinical status as severe (n=91), moderate (n=56) and mild (n=170). Of these patients, 92 had acute COVID-19 at sample collection, 90 had already recovered from COVID-19 without sequelae, and 135 had sequelae (long COVID syndrome). In the acute COVID-19 group, patients with the severe form had higher IL-6 levels (p=0.0260). In the post-COVID-19 group, there was no significant difference in cytokine levels between groups with different clinical conditions. In the acute COVID-19 group, younger patients had higher levels of TNF-α, and patients without comorbidities had higher levels of TNF-α, IL-4 and IL-2 (p<0.05). In contrast, patients over age 60 with comorbidities had higher levels of IL-6. In the post-COVID-19 group, subjects with long COVID-19 had higher levels of IL-17 and IL-2 (p<0.05), and subjects without sequelae had higher levels of IL-10, IL-6 and IL- 4 (p<0.05). Our results suggest that advanced age, comorbidities and elevated serum IL-6 levels are associated with severe COVID-19 and are good markers to differentiate severe from mild cases. Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 and IL-10 appear to constitute a cytokine profile of long COVID-19, and these markers are potential targets for COVID-19 treatment and prevention strategies.

Predictive immunogenetic markers in COVID-19.

Immunorelevant genes are among the most probable modulators of coronavirus disease 2019 (COVID-19) progression and prognosis. However, in the few months of the pandemic, data generated on host genetics has been scarce. The present study retrieved data sets of HLA-B alleles, KIR genes and functional single nucleotide polymorphisms (SNPs) in cytokines related to COVID-19 cytokine storm from two publicly available databases: Allele Frequency Net Database and Ensembl, and correlated these frequency data with Case Fatality Rate (CFR) and Daily Death Rates (DDR) across countries. Correlations of eight HLA-B alleles and polymorphisms in three cytokine genes (IL6, IL10, and IL12B) were observed and were mainly associated with DDR. Additionally, HLA-B correlations suggest that differences in allele affinities to SARS-CoV-2 peptides are also associated with DDR. These results may provide rationale for future host genetic marker surveys on COVID-19.

How natural selection shapes genetic differentiation in the MHC region: A case study with Native Americans.

The Human Leukocyte Antigen (HLA) loci are extremely well documented targets of balancing selection, yet few studies have explored how selection affects population differentiation at these loci. In the present study we investigate genetic differentiation at HLA genes by comparing differentiation at microsatellites distributed genomewide to those in the MHC region. Our study uses a sample of 494 individuals from 30 human populations, 28 of which are Native Americans, all of whom were typed for genomewide and MHC region microsatellites. We find greater differentiation in the MHC than in the remainder of the genome (FST-MHC = 0.130 and FST-Genomic = 0.087), and use a permutation approach to show that this difference is statistically significant, and not accounted for by confounding factors. This finding lies in the opposite direction to the expectation that balancing selection reduces population differentiation. We interpret our findings as evidence that selection favors different sets of alleles in distinct localities, leading to increased differentiation. Thus, balancing selection at HLA genes simultaneously increases intra-population polymorphism and inter-population differentiation in Native Americans.