Two-year Decay of Zika Virus Neutralizing Antibodies in People Living in an Endemic Region in Brazil.

It is currently not clear whether humoral immunity to Zika virus (ZIKV) elicited upon natural ZIKV infection is long-lasting. In addition, cross-reactivity of anti-ZIKV antibodies with antigenically related dengue viruses (DENV) may have biological implications in nonnaive individuals who subsequently acquire a heterotypic infection. Cross-reactive humoral immunity between ZIKV and DENV also complicates the interpretation of serological tests to evaluate previous exposure to either virus. Here, we have measured the 2-year decay of ZIKV neutralizing antibodies in people living in a ZIKV/DENV endemic area in Brazil who were identified as having an acute infection (group 1) or past (but recent) infection (group 2) with ZIKV in 2015-16. The titers of neutralizing antibodies to ZIKV decreased 9.1 and 2.3 times in groups 1 and 2, respectively. We also show that the plaque reduction neutralization assay (PRNT) is a reliable method to measure past exposure to ZIKV in coendemic areas.

The P-MAPA Immunomodulator Partially Prevents Apoptosis Induced by Zika Virus Infection in THP-1 Cells.

BACKGROUND: Zika virus is an emerging arbovirus of global importance. ZIKV infection is associated with a range of neurological complications such as the Congenital Zika Syndrome and Guillain Barré Syndrome. Despite the magnitude of recent outbreaks, there is no specific therapy to prevent or to alleviate disease pathology. OBJECTIVE: To investigate the role of P-MAPA immunomodulator in Zika-infected THP-1 cells. METHODS: THP-1 cells were subjected to Zika virus infection (Multiplicity of Infection = 0.5) followed by treatment with P-MAPA for until 96 hours post-infection. After that, the cell death was analyzed by annexin+/ PI+ and caspase 3/ 7+ staining by flow cytometry. In addition, virus replication and cell proliferation were accessed by RT-qPCR and Ki67 staining, respectively. RESULTS: We demonstrate that P-MAPA in vitro treatment significantly reduces Zika virus-induced cell death and caspase-3/7 activation on THP-1 infected cells, albeit it has no role in virus replication and cell proliferation. CONCLUSION: Our study reveals that P-MAPA seems to be a satisfactory alternative to inhibit the effects of Zika virus infection in mammalian cells.

Follow-Up Household Serosurvey in Northeast Brazil for Zika Virus: Sexual Contacts of Index Patients Have the Highest Risk for Seropositivity.

BACKGROUND: Zika virus (ZIKV) is a mosquito-borne virus that is also transmitted sexually; however, the epidemiological relevance of ZIKV sexual transmission in endemic regions is unclear. METHODS: We performed a household-based serosurvey in Northeast Brazil to evaluate the differential exposure to ZIKV and chikungunya virus (CHIKV) among households. Individuals who participated in our previous arboviral disease cohort (indexes) were recontacted and enrolled, and their household members were newly enrolled. RESULTS: The relative risk of sexual partners being ZIKV-seropositive when living with a ZIKV-seropositive index participant was significantly higher, whereas this was not observed among nonsexual partners of the index. For CHIKV, both sexual and nonsexual partner household members living with a CHIKV-seropositive index had a significantly higher risk of being seropositive. In the nonindex-based dyadic and generalized linear mixed model analyses, the odds of sexual dyads having a concordant ZIKV plaque reduction neutralization test result was significantly higher. We have also analyzed retrospective clinical data according to the participants' exposure to ZIKV and CHIKV. CONCLUSIONS: Our data suggest that ZIKV sexual transmission may be a key factor for the high ZIKV seroprevalence among households in endemic areas and raises important questions about differential disease from the 2 modes of transmission.

The Transcriptional and Protein Profile From Human Infected Neuroprogenitor Cells Is Strongly Correlated to Zika Virus Microcephaly Cytokines Phenotype Evidencing a Persistent Inflammation in the CNS.

Zika virus (ZIKV) infection during pregnancy is associated with microcephaly, a congenital malformation resulting from neuroinflammation and direct effects of virus replication on the developing central nervous system (CNS). However, the exact changes in the affected CNS remain unknown. Here, we show by transcriptome analysis (at 48 h post-infection) and multiplex immune profiling that human induced-neuroprogenitor stem cells (hiNPCs) respond to ZIKV infection with a strong induction of type-I interferons (IFNs) and several type-I IFNs stimulated genes (ISGs), notably cytokines and the pro-apoptotic chemokines CXCL9 and CXCL10. By comparing the inflammatory profile induced by a ZIKV Brazilian strain with an ancestral strain isolated from Cambodia in 2010, we observed that the response magnitude differs among them. Compared to ZIKV/Cambodia, the experimental infection of hiNPCs with ZIKV/Brazil resulted in a diminished induction of ISGs and lower induction of several cytokines (IFN-α, IL-1α/ß, IL-6, IL-8, and IL-15), consequently favoring virus replication. From ZIKV-confirmed infant microcephaly cases, we detected a similar profile characterized by the presence of IFN-α, CXCL10, and CXCL9 in cerebrospinal fluid (CSF) samples collected after birth, evidencing a sustained CNS inflammation. Altogether, our data suggest that the CNS may be directly affected due to an unbalanced and chronic local inflammatory response, elicited by ZIKV infection, which contributes to damage to the fetal brain.

Dengue Virus-Specific Antibodies Enhance Brazilian Zika Virus Infection.

Anti-Flavivirus antibodies are highly cross-reactive and may facilitate Zika virus (ZIKV) infection through the antibody-dependent enhancement (ADE) mechanism. We demonstrate that dengue-specific antibodies enhance the infection of a primary Brazilian ZIKV isolate in a FcγRII-expressing K562 cell line. In addition, we demonstrate that serum samples from dengue-immune pregnant women enhanced ZIKV infection. These findings highlight the need for epidemiological studies and animal models to further confirm the role of ADE in the development of congenital and neurological complications associated with ZIKV infections.

ΔNp73 overexpression promotes resistance to apoptosis but does not cooperate with PML/RARA in the induction of an APL-leukemic phenotype.

Here, we evaluated whether the overexpression of transcriptionally inactive ΔNp73 cooperates with PML/RARA fusion protein in the induction of an APL-leukemic phenotype, as well as its role in vitro in proliferation, myeloid differentiation, and drug-induced apoptosis. Using lentiviral gene transfer, we showed in vitro that ΔNp73 overexpression resulted in increased proliferation in murine bone marrow (BM) cells from hCG-PML/RARA transgenic mice and their wild-type (WT) counterpart, with no accumulation of cells at G2/M or S phases; instead, ΔNp73-expressing cells had a lower rate of induced apoptosis. Next, we evaluated the effect of ΔNp73 on stem-cell self-renewal and myeloid differentiation. Primary BM cells lentivirally infected with human ΔNp73 were not immortalized in culture and did not present significant changes in the percentage of CD11b. Finally, we assessed the impact of ΔNp73 on leukemogenesis or its possible cooperation with PML/RARA fusion protein in the induction of an APL-leukemic phenotype. After 120 days of follow-up, all transplanted mice were clinically healthy and, no evidence of leukemia/myelodysplasia was apparent. Taken together, our data suggest that ΔNp73 had no leukemic transformation capacity by itself and apparently did not cooperate with the PML/RARA fusion protein to induce a leukemic phenotype in a murine BM transplantation model. In addition, the forced expression of ΔNp73 in murine BM progenitors did not alter the ATRA-induced differentiation rate in vitro or induce aberrant cell proliferation, but exerted an important role in cell survival, providing resistance to drug-induced apoptosis.

Genetic susceptibility to chronic Chagas disease: an overview of single nucleotide polymorphisms of cytokine genes.

Chagas disease is a parasitic infection that is a significant public health problem in Latin America. The mechanisms responsible for susceptibility to the infection and the mechanisms involved in the development of cardiac and digestive forms of chronic Chagas disease remain poorly understood. However, there is growing evidence that differences in susceptibility in endemic areas may be attributable to host genetic factors. The aim of this overview was to analyze the genetic susceptibility to human Chagas disease, particularly that of single nucleotide polymorphisms of cytokine genes. A review of the literature was conducted on the following databases: PubMed/MEDLINE and Scopus. The search strategy included using the following terms: "Cytokines", "Single Nucleotide Polymorphisms" and "Chagas Disease". After screening 25 citations from the databases, 19 studies were selected for the overview. A critical analysis of the data presented in the articles suggests that genetic susceptibility to Chagas disease and chronic Chagas cardiomyopathy is highly influenced by the complexity of the immune response of the host. Follow-up studies based on other populations where Chagas disease is endemic (with distinct ethnic and genetic backgrounds) need to be conducted. These should use a large sample population so as to establish what cytokine genes are involved in susceptibility to and/or progression of the disease.

Immunoglobulin M antibodies against CRA and FRA recombinant antigens of Trypanosoma cruzi in chronic chagasic patients.

Previous works of our research group have demonstrated aspects of the humoral immune response of chronic Chagas disease using the cytoplasmatic repetitive antigen (CRA) and the flagellar repetitive antigen (FRA) of Trypanosoma cruzi. The aim of this work was to analyze the presence of specific immunoglobulin M (IgM) antibodies in chronic chagasic patients using these recombinant antigens of T. cruzi. The positivity of IgM in chronic chagasic patients against CRA and FRA antigens was determined by indirect enzyme-linked immunosorbent assay. We reported no statistical significant differences between the levels of IgM for both recombinant antigens and the different chronic clinical forms of Chagas disease. However, a small proportion of chronic chagasic patients analyzed in this study was positive for this antibody isotype. The findings of this study indicate that the IgM antibodies cannot be used to elucidate the differences in the profile of humoral immune response among chronic chagasic patients with different clinical forms using the CRA and FRA recombinant antigens of T. cruzi.