Aspectos imunológicos associados à ocorrência e gravidade da síndrome congênita do vírus Zika e à recorrência da COVID-19

Abstract

Zika virus infections are usually asymptomatic or cause mild, self-limited illness, however, severe infections such as congenital Zika syndrome (CZS) in neonates can occur. Most SARS-CoV-2 infections also cause mild illness, but its rapid and widespread distribution has led to cases of disease recurrence. These atypical outcomes occur in a small number of infected people and the determining factors for their occurrence are poorly understood Variations in the immune response influence susceptibility or resistance to disease. Considering this, the aims of this thesis were to evaluate the association between single nucleotide polymorphisms (SNPs) in candidate genes with Zika virus infection and the occurrence of congenital Zika syndrome (Chapter I). For this, a case-control study was conducted, in which the case group was composed of children with SCZ and their mothers, and the control group, composed of healthy children who were born in the same place and period of the Zika virus outbreak and their mothers. Genomic DNA from patients and controls was obtained and used in the genotyping of the SNPs in the TREM1, CXCL10, IL4, CXCL8, TLR3, TLR7, IFNR1, IFNγ, CXCR1, IL10, CCR2 and CCR5 genes, and the association with Zika virus infection and the SCZ has been verified. The results showed an association between the SNPs TREM1 rs2234246 and IL4 rs224325 in mothers and the occurrence of SCZ, when compared to mothers in the control group. Furthermore, the SNPs CXCL10 rs4508917 and CXCL8 rs4073 were associated with the presence of SCZ, and the SNPs CXCL8 rs4073 and TRL7 rs179008 were associated with the severity of microcephaly due to SCZ. For the study described in Chapter II, a case series study with a control group was carried out, comparing the specific immune response of groups of patients with recurrence, a single episode or no history of COVID-19, in which peripheral blood mononuclear cells were stimulated with the S1 protein of SARS-CoV-2 and the phenotype of CD4+ and CD8+ multifunctional T cells was evaluated, by the production of IFN-γ and/or IL-2 and/or TNF-α, by flow cytometry. Lymphocyte evaluation showed that SARS-CoV-2 S1 protein can stimulate cytokine production in CD4+ and CD8+ T lymphocytes in the analyzed patient groups, with no significant differences in the total percentage of cells, between groups of patients with recurrent COVID-19 or with a single episode, either before or after vaccination . However, patients who had COVID-19 and tested positive for anti-S1 IgG produced more CD4 CD4+IFN-γ+IL-2+TNF-α+ cells than those who had the disease and were negative for IgG anti-S1. In addition, vaccination promoted a significant increase in the production of IgG- type antibodies to the SARS-CoV-2 S1 protein in all groups and promoted a change in the phenotypic pattern of T lymphocytes for the evaluated cytokines. In conclusion, the results suggest that maternal genetics is an important factor for the occurrence of SCZ and, likewise, that conceptus genetics may contribute to both the occurrence and severity of SCZ. Furthermore, the data suggest that multifunctional T cells producing IFN-γ, IL-2 and TNF-α, double or triple positive for these cytokines, are not a relevant factor for the occurrence of COVID-19 recurrences. Together, the data contribute to a better understanding of the host's immune response and its relationship with different outcomes in the Zika virus and SARSCoV-2 infections.