Despite the high number of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) symptoms worldwide, many exposed individuals remain asymptomatic and/or uninfected and seronegative. This could be explained by a combination of environmental (exposure), immunological (previous infection), epigenetic, and genetic factors. Aiming to identify genetic factors involved in immune response in symptomatic COVID-19 as compared to asymptomatic exposed individuals, we analyzed 83 Brazilian couples where one individual was infected and symptomatic while the partner remained asymptomatic and serum-negative for at least 6 months despite sharing the same bedroom during the infection. We refer to these as “discordant couples”. We performed whole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic major histocompatibility complex (MHC) region. The discordant partners had comparable ages and genetic ancestry, but women were overrepresented (65%) in the asymptomatic group. In the antigen-presentation pathway, we observed an association between HLA-DRB1 alleles encoding Lys at residue 71 (mostly DRB1*03:01 and DRB1*04:01) and DOB*01:02 with symptomatic infections and HLA-A alleles encoding 144Q/151R with asymptomatic seronegative women. Among the genes related to immune modulation, we detected variants in MICA and MICB associated with symptomatic infections. These variants are related to higher expression of soluble MICA and low expression of MICB. Thus, quantitative differences in these molecules that modulate natural killer (NK) activity could contribute to susceptibility to COVID-19 by downregulating NK cell cytotoxic activity in infected individuals but not in the asymptomatic partners.

We investigated whether stress interferes with fertility during adulthood. Male Wistar rats (weighing 220 g in the beginning of the experiment) were forced to swim for 3 min in water at 32ºC daily for 15 days. Stress was assessed by the hot-plate test after the last stressing session. To assess fertility, control and stressed males (N = 15 per group) were mated with sexually mature normal females. Males were sacrificed after copulation. Stress caused by forced swimming was demonstrated by a significant increase in the latency of the pain response in the hot-plate test (14.6 ± 1.25 s for control males vs 26.0 ± 1.53 s for stressed males, P = 0.0004). No changes were observed in body weight, testicular weight, seminal vesicle weight, ventral prostate weight or gross histological features of the testes of stressed males. Similarly, no changes were observed in fertility rate, measured by counting live fetuses in the uterus of normal females mated with control and stressed males; no dead or incompletely developed fetuses were observed in the uterus of either group. In contrast, there was a statistically significant decrease in spermatid production demonstrated by histometric evaluation (154.96 ± 5.41 vs 127.02 ± 3.95 spermatids per tubular section for control and stressed rats, respectively, P = 0.001). These data demonstrate that 15 days of forced swimming stress applied to adult male rats did not impair fertility, but significantly decreased spermatid production. This suggests that the effect of stress on fertility should not be assessed before at least the time required for one cycle of spermatogenesis.

BackgroundAlthough aging correlates with a worse prognosis for Covid-19, super elderly still unvaccinated individuals presenting mild or no symptoms have been reported worldwide. Most of the reported genetic variants responsible for increased disease susceptibility are associated with immune response, involving type I IFN immunity and modulation; HLA cluster genes; inflammasome activation; genes of interleukins; and chemokines receptors. On the other hand, little is known about the resistance mechanisms against SARS-CoV-2 infection. Here, we addressed polymorphisms in the MHC region associated with Covid-19 outcome in super elderly resilient patients as compared to younger patients with a severe outcome.MethodsSARS-CoV-2 infection was confirmed by RT-PCR test. Aiming to identify candidate genes associated with host resistance, we investigated 87 individuals older than 90 years who recovered from Covid-19 with mild symptoms or who remained asymptomatic following positive test for SARS-CoV-2 as compared to 55 individuals younger than 60 years who had a severe disease or died due to Covid-19, as well as to the general elderly population from the same city. Whole-exome sequencing and an in-depth analysis of the MHC region was performed. All samples were collected in early 2020 and before the local vaccination programs started.ResultsWe found that the resilient super elderly group displayed a higher frequency of some missense variants in the MUC22 gene (a member of the mucins’ family) as one of the strongest signals in the MHC region as compared to the severe Covid-19 group and the general elderly control population. For example, the missense variant rs62399430 at MUC22 is two times more frequent among the resilient super elderly (p = 0.00002, OR = 2.24).ConclusionSince the pro-inflammatory basal state in the elderly may enhance the susceptibility to severe Covid-19, we hypothesized that MUC22 might play an important protective role against severe Covid-19, by reducing overactive immune responses in the senior population.

BackgroundDespite the high number of individuals infected by SARS-CoV-2 who develop COVID-19 symptoms worldwide, many exposed individuals remain asymptomatic and/or stay uninfected. This could be explained by a combination of environmental (exposure, previous infection), epigenetic, and genetic factors. Aiming to identify genetic variants involved in SARS-CoV-2 resistance, we analyzed 86 discordant Brazilian couples where one was infected and symptomatic while the partner remained asymptomatic and seronegative despite sharing the same bedroom during the infection. The discordant partners had comparable ages, and genetic ancestry proportions.MethodsWhole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic MHC and LRC.ResultsWe observed a minor impact in antigen-presentation genes and KIR genes associated with resistance. Interestingly, genes related to immune modulation, mainly involved in NK cell killing activation/inhibition harbor variants potentially contributing to infection resistance. We hypothesize that individuals prone to produce higher amounts of MICA (possibly soluble), LILRB1, LILRB2, and low amounts of MICB, would be more susceptible to infection.ConclusionAccording to this hypothesis, quantitative differences in these NK activity-related molecules could contribute to resistance to COVID-19 down regulating NK cell cytotoxic activity in infected individuals but not in resistant partners.

HLA‐B is among the most variable gene in the human genome. This gene encodes a key molecule for antigen presentation to CD8+ T lymphocytes and NK cell modulation. Despite the myriad of studies evaluating its coding region (with an emphasis on exons 2 and 3), few studies evaluated introns and regulatory sequences in real population samples. Thus, HLA‐B variability is probably underestimated. We applied a bioinformatics pipeline tailored for HLA genes on 5347 samples from 80 different populations, which includes more than 1000 admixed Brazilians, to evaluate the HLA‐B variability (SNPs, indels, MNPs, alleles, and haplotypes) in exons, introns, and regulatory regions. We observed 610 variable sites throughout HLA‐B; the most frequent variants are shared worldwide. However, the haplotype distribution is geographically structured. We detected 920 full‐length haplotypes (exons, introns, and untranslated regions) encoding 239 different protein sequences. HLA‐B gene diversity is higher in admixed populations and Europeans while lower in African ancestry individuals. Each HLA‐B allele group is associated with specific promoter sequences. This HLA‐B variation resource may improve HLA imputation accuracy and disease‐association studies and provide evolutionary insights regarding HLA‐B genetic diversity in human populations.

O LES desenvolve-se a partir da interação entre fatores ambientais, como exposição ao sol, estresse físico ou emocional, e fatores imunogenéticos. O sistema imunológico tem como função o desenvolvimento de respostas imunológicas a partir da detecção de antígenos. Este processo ocorre em duas etapas, sendo: apresentação de antígenos, através de moléculas de histocompatibilidade (HLA, do inglês human leucocytes antigen), e detecção e interpretação destes por linfócitos T. Assim, o objetivo deste trabalho foi descrever o papel das moléculas de HLA no desenvolvimento de LES.  Polimorfismos nas moléculas de HLA podem influenciar no processo de autotolerância de linfócitos T e, consequentemente, desencadear resposta inflamatória contra o próprio organismo, característico de doenças autoimunes. Desta forma, pesquisas imunogenéticas são de suma importância para melhor compreensão da doença, pois fornecem informações sobre marcadores genéticos associados ao LES, proporcionando a análise de fatores de risco ou proteção à doença, entre diferentes etnias, auxiliando na identificação de marcadores genéticos universais e contribuindo, assim, para diagnóstico e tratamento mais precoces.

RESUMOMudanças climáticas são previstas para as próximas décadas e, consequentemente, seus impactos na pecuária bovina, sendo a seleção nos rebanhos uma maneira de amenizá-los. Este trabalho teve como objetivo desenvolver um sistema de seleção baseado nos parâmetros genéticos gerados por modelos de norma de reação adaptativa em bovinos da raça Nelore. Foram utilizados dados genealógicos e de crescimento fornecidos pela Associação Brasileira de Criadores de Bovinos. Definiu-se um gradiente ambiental baseado em valores médios de grupos contemporâneos padronizados. Para a predição de coeficientes das normas de reação adaptativas utilizou-se a regressão aleatória com polinômios cúbicos para pesos aos 450 dias com análise de sexos separados. Foram calculados os valores genéticos dos diferentes indivíduos em função de um gradiente ambiental utilizando o software BLUPF90. Os indivíduos foram classificados considerando coeficientes que gerassem normas com valores genéticos elevados e com menor variação ao longo do gradiente ambiental. Compensou-se, então, a elevação do valor genético e a sua robustez, criando clusters de robustez (CRs) com base na comparação direta entre os coeficientes. Os resultados da classificação mostraram que a seleção de indivíduos das classes de maior robustez devem gerar progênies com menor sensibilidade ambiental, visto que os coeficientes são componentes genéticos aditivos. Conclui-se que a seleção por clusters de robustez é uma forma de amenizar os impactos produzidos nos sistemas de produção por alterações nos ambientes de criação.Palavras-chave: norma de reação, sensibilidade ambiental, mitigação, mudanças climáticas. ROBUSTNESS CLUSTERS AS SELECTION CRITERIUM IN GENETIC IMPROVEMENT FOR MITIGATION OF THE IMPACTS OF CLIMATE CHANGE ABSTRACTClimate changes are expected for the next decades and, consequently, their impacts on cattle breeding, with artificial selection a possible method to mitigate them. This work aimed to develop a selection system based on the genetic parameters generated by adaptive reaction norm models in Nellore cattle. Genetic and growth data were provided by the Brazilian Association of Cattle Breeders. An environmental gradient was created using contemporary group averages standardized to a mean of zero and standard deviation of one. For the prediction of coefficients of the adaptive reaction norms, the random regression model was *

Os genes MICA e MICB codificam as glicoproteínas expressas constitutivamente em fibroblastos e células epiteliais, no entanto, são sintetizadas como marcadores de estresse celular em condições como o câncer, infecções e doenças autoimunes. Portanto, o objetivo do presente estudo foi descrever, através de uma revisão bibliográfica, a associação entre os genes MICA e MICB e infecções por patógenos intracelulares. Diversos estudos mostraram a associação desses genes com a suscetibilidade ou proteção à algumas doenças causadas por patógenos intracelulares, como por exemplo, os alelos MICA*045 e MICA*008, que foram associados com a suscetibilidade a dengue, enquanto o alelo MICB*002 com a proteção à doença. Na hanseníase, um estudo sugere o alelo MICA*008:01 como protetor da doença. Enquanto na doença de Chagas, foram observados os alelos MICA*007, MICA*008, e o haplótipo MICA*008_HLA-B*08. Quanto a tuberculose, os genes MICA-A4, MICA*012:01 e MICB*008 são mais frequentemente encontrados em portadores da doença, ao contrário do MICA-A5, que pouco é observado nestes pacientes. Indivíduos propensos a produzir maiores quantidades de MICA (possivelmente solúvel) e baixas quantidades de MICB (rs3131639/A e MICB*004:01) seriam mais suscetíveis à infecção por Sars-Cov-2. Portanto, os genes MICA e MICB podem estar relacionados à predisposição ou resistência à diversas doenças.