KEITY SOUZA SANTOS
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/19 - Laboratório de Histocompatibilidade e Imunidade Celular, Hospital das Clínicas, Faculdade de Medicina - Líder
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conferenceObject Immune Responses Of CVID Patients To COVID-19 Vaccines(2023) MEDEIROS, Giuliana Xavier de; FERREIRA, Loisi de Carvalho Pereira; MAGAWA, Jhosiene Yukari; KURAMOTO, Andreia; SASAHARA, Greyce Luri; FERREIRA, Marcelo; BARROS, Myrthes Maragna Toledo; KALIL, Jorge; MARINHO, Ana Karolina Barreto Berselli; CUNHA-NETO, Edecio; SANTOS, Keity Souza; KOKRON, Cristina- Immunodominant antibody responses directed to SARS-CoV-2 hotspot mutation sites and risk of immune escape(2023) OLIVEIRA, Jamille Ramos; RUIZ, Cesar Manuel Remuzgo; MACHADO, Rafael Rahal Guaragna; MAGAWA, Jhosiene Yukari; DAHER, Isabela Pazotti; URBANSKI, Alysson Henrique; SCHMITZ, Gabriela Justamante Haendel; ARCURI, Helen Andrade; FERREIRA, Marcelo Alves; SASAHARA, Greyce Luri; MEDEIROS, Giuliana Xavier de; JR, Roberto Carlos Vieira Silva; DURIGON, Edison Luiz; BOSCARDIN, Silvia Beatriz; ROSA, Daniela Santoro; SCHECHTMAN, Deborah; NAKAYA, Helder. I. I.; CUNHA-NETO, Edecio; GADERMAIER, Gabriele; KALIL, Jorge; COELHO, Veronica; SANTOS, Keity SouzaIntroductionConsidering the likely need for the development of novel effective vaccines adapted to emerging relevant CoV-2 variants, the increasing knowledge of epitope recognition profile among convalescents and afterwards vaccinated with identification of immunodominant regions may provide important information. MethodsWe used an RBD peptide microarray to identify IgG and IgA binding regions in serum of 71 COVID-19 convalescents and 18 vaccinated individuals. ResultsWe found a set of immunodominant RBD antibody epitopes, each recognized by more than 30% of the tested cohort, that differ among the two different groups and are within conserved regions among betacoronavirus. Of those, only one peptide, P44 (S415-429), recognized by 68% of convalescents, presented IgG and IgA antibody reactivity that positively correlated with nAb titers, suggesting that this is a relevant RBD region and a potential target of IgG/IgA neutralizing activity. DiscussionThis peptide is localized within the area of contact with ACE-2 and harbors the mutation hotspot site K417 present in gamma (K417T), beta (K417N), and omicron (K417N) variants of concern. The epitope profile of vaccinated individuals differed from convalescents, with a more diverse repertoire of immunodominant peptides, recognized by more than 30% of the cohort. Noteworthy, immunodominant regions of recognition by vaccinated coincide with mutation sites at Omicron BA.1, an important variant emerging after massive vaccination. Together, our data show that immune pressure induced by dominant antibody responses may favor hotspot mutation sites and the selection of variants capable of evading humoral response.
- MUC22, HLA-A, and HLA-DOB variants and COVID-19 in resilient super-agers from Brazil(2022) CASTELLI, Erick C.; CASTRO, Mateus V. de; NASLAVSKY, Michel S.; SCLIAR, Marilia O.; SILVA, Nayane S. B.; PEREIRA, Raphaela N.; CIRIACO, Viviane A. O.; CASTRO, Camila F. B.; MENDES-JUNIOR, Celso T.; SILVEIRA, Etiele de S.; OLIVEIRA, Iuri M. de; ANTONIO, Eduardo C.; VIEIRA, Gustavo F.; MEYER, Diogo; NUNES, Kelly; MATOS, Larissa R. B.; SILVA, Monize V. R.; WANG, Jaqueline Y. T.; ESPOSITO, Joyce; CORIA, Vivian R.; MAGAWA, Jhosiene Y.; SANTOS, Keity S.; CUNHA-NETO, Edecio; KALIL, Jorge; BORTOLIN, Raul H.; HIRATA, Mario Hiroyuki; DELL'AQUILA, Luiz P.; RAZUK-FILHO, Alvaro; BATISTA-JUNIOR, Pedro B.; DUARTE-NETO, Amaro N.; DOLHNIKOFF, Marisa; SALDIVA, Paulo H. N.; PASSOS-BUENO, Maria Rita; ZATZ, MayanaBackgroundAlthough 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.
- Immunological evaluation of young unvaccinated patients with Turner syndrome after COVID-19(2023) CASTRO, Mateus V. de; SILVA, Monize V. R.; OLIVEIRA, Luana de M.; GOZZI-SILVA, Sarah C.; NASLAVSKY, Michel S.; SCLIAR, Marilia O.; MAGALHAES, Monize L.; ROCHA, Katia M. da; NUNES, Kelly; CASTELLI, Erick C.; MAGAWA, Jhosiene Y.; SANTOS, Keity S.; CUNHA-NETO, Edecio; SATO, Maria N.; ZATZ, MayanaObjectives: The X-chromosome contains the largest number of immune-related genes, which play a major role in COVID-19 symptomatology and susceptibility. Here, we had a unique opportunity to investigate, for the first time, COVID-19 outcomes in six unvaccinated young Brazilian patients with Turner syndrome (TS; 45, X0), including one case of critical illness in a child aged 10 years, to evaluate their immune response according to their genetic profile. Methods: A serological analysis of humoral immune response against SARS-CoV-2, phenotypic character-ization of antiviral responses in peripheral blood mononuclear cells after stimuli, and the production of cytotoxic cytokines of T lymphocytes and natural killer cells were performed in blood samples collected from the patients with TS during the convalescence period. Whole exome sequencing was also performed.Results: Our volunteers with TS showed a delayed or insufficient humoral immune response to SARS-CoV-2 (particularly immunoglobulin G) and a decrease in interferon-gamma production by cluster of differentiation (CD)4 + and CD8 + T lymphocytes after stimulation with toll-like receptors 7/8 agonists. In contrast, we observed a higher cytotoxic activity in the volunteers with TS than the volunteers without TS after phor-bol myristate acetate/ionomycin stimulation, particularly granzyme B and perforin by CD8 + and natural killer cells. Interestingly, two volunteers with TS carry rare genetic variants in genes that regulate type I and III interferon immunity.Conclusion: Following previous reports in the literature for other conditions, our data showed that pa-tients with TS may have an impaired immune response against SARS-CoV-2. Furthermore, other medical conditions associated with TS could make them more vulnerable to COVID-19.(c) 2023 The Author(s).
- Recurrence of COVID-19 associated with reduced T-cell responses in a monozygotic twin pair(2022) V, Mateus de Castro; SANTOS, Keity S.; APOSTOLICO, Juliana S.; FERNANDES, Edgar R.; ALMEIDA, Rafael R.; LEVIN, Gabriel; MAGAWA, Jhosiene Y.; NUNES, Joao Paulo S.; BRUNI, Mirian; YAMAMOTO, Marcio M.; LIMA, Ariane C.; SILVA, Monize V. R.; MATOS, Larissa R. B.; CORIA, Vivian R.; CASTELLI, Erick C.; SCLIAR, Marilia O.; KURAMOTO, Andreia; BRUNO, Fernanda R.; JACINTHO, Lucas C.; NUNES, Kelly; WANG, Jaqueline Y. T.; COELHO, Veronica P.; NETO, Miguel Mitne; MACIEL, Rui M. B.; NASLAVSKY, Michel S.; PASSOS-BUENO, Maria Rita; BOSCARDIN, Silvia B.; ROSA, Daniela S.; KALIL, Jorge; ZATZ, Mayana; CUNHA-NETO, EdecioRecurrence of COVID-19 in recovered patients has been increasingly reported. However, the immune mechanisms behind the recurrence have not been thoroughly investigated. The presence of neutralizing antibodies (nAbs) in recurrence/reinfection cases suggests that other types of immune response are involved in protection against recurrence. Here, we investigated the innate type I/III interferon (IFN) response, binding and nAb assays and T-cell responses to severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) with IFN gamma (IFN gamma) enzyme-linked spot assay (ELISPOT) in three pairs of young adult monozygotic (MZ) twins with previous confirmed COVID-19, one of them presenting a severe recurrence four months after the initial infection. Twin studies have been of paramount importance to comprehend the immunogenetics of infectious diseases. Each MZ twin pair was previously exposed to SARS-CoV-2, as seen by clinical reports. The six individuals presented similar overall recovered immune responses except for the recurrence case, who presented a drastically reduced number of recognized SARS-CoV-2 T-cell epitopes on ELISPOT as compared to her twin sister and the other twin pairs. Our results suggest that the lack of a broad T-cell response to initial infection may have led to recurrence, emphasizing that an effective SARS-CoV-2-specific T-cell immune response is key for complete viral control and avoidance of clinical recurrence of COVID-19.
- The oldest unvaccinated Covid-19 survivors in South America(2022) V, Mateus de Castro; SILVA, Monize V. R.; NASLAVSKY, Michel S.; SCLIAR, Marilia O.; NUNES, Kelly; PASSOS-BUENO, Maria Rita; CASTELLI, Erick C.; MAGAWA, Jhosiene Y.; ADAMI, Flavia L.; MORETTI, Ana I. S.; OLIVEIRA, Vivian L. de; BOSCARDIN, Silvia B.; CUNHA-NETO, Edecio; KALIL, Jorge; JOUANGUY, Emmanuelle; BASTARD, Paul; CASANOVA, Jean-Laurent; QUINONES-VEGA, Mauricio; SOSA-ACOSTA, Patricia; GUEDES, Jessica S. de; ALMEIDA, Natalia P. de; NOGUEIRA, Fabio C. S.; DOMONT, Gilberto B.; SANTOS, Keity S.; ZATZ, MayanaBackground Although older adults are at a high risk of severe or critical Covid-19, there are many cases of unvaccinated centenarians who had a silent infection or recovered from mild or moderate Covid-19. We studied three Brazilian supercentenarians, older than 110 years, who survived Covid-19 in 2020 before being vaccinated. Results Despite their advanced age, humoral immune response analysis showed that these individuals displayed robust levels of IgG and neutralizing antibodies (NAbs) against SARS-CoV-2. Enrichment of plasma proteins and metabolites related to innate immune response and host defense was also observed. None presented autoantibodies (auto-Abs) to type I interferon (IFN). Furthermore, these supercentenarians do not carry rare variants in genes underlying the known inborn errors of immunity, including particular inborn errors of type I IFN. Conclusion These observations suggest that their Covid-19 resilience might be a combination of their genetic background and their innate and adaptive immunity.
- The oldest unvaccinated Covid-19 survivors in South America (vol 19, 57, 2022)(2022) CASTRO, Mateus V. V. de; SILVA, Monize V. R.; NASLAVSKY, Michel S. S.; SCLIAR, Marilia O. O.; NUNES, Kelly; PASSOS-BUENO, Maria Rita; CASTELLI, Erick C. C.; MAGAWA, Jhosiene Y. Y.; ADAMI, Flavia L.; MORETTI, Ana I. S.; OLIVEIRA, Vivian L. L. de; BOSCARDIN, Silvia B. B.; CUNHA-NETO, Edecio; KALIL, Jorge; JOUANGUY, Emmanuelle; BASTARD, Paul; CASANOVA, Jean-Laurent; QUINONES-VEGA, Mauricio; SOSA-ACOSTA, Patricia; GUEDES, Jessica de S.; ALMEIDA, Natalia P. de; NOGUEIRA, Fabio C. S.; DOMONT, Gilberto B. B.; SANTOS, Keity S. S.; ZATZ, Mayana
- Reduced T Cell and Antibody Responses to Inactivated Coronavirus Vaccine Among Individuals Above 55 Years Old(2022) MEDEIROS, Giuliana X.; SASAHARA, Greyce Luri; MAGAWA, Jhosiene Y.; NUNES, Joao Paulo S.; BRUNO, Fernanda R.; KURAMOTO, Andreia C.; ALMEIDA, Rafael R.; FERREIRA, Marcelo A.; SCAGION, Guilherme P.; CANDIDO, Erika D.; LEAL, Fabyano B.; OLIVEIRA, Danielle B. L.; DURIGON, Edison L.; SILVA JR., Roberto Carlos V.; ROSA, Daniela S.; BOSCARDIN, Silvia B.; COELHO, Veronica; KALIL, Jorge; SANTOS, Keity S.; CUNHA-NETO, EdecioCoronaVac is an inactivated SARS-CoV-2 vaccine that has been rolled out in several low and middle-income countries including Brazil, where it was the mainstay of the first wave of immunization of healthcare workers and the elderly population. We aimed to assess the T cell and antibody responses of vaccinated individuals as compared to convalescent patients. We detected IgG against SARS-CoV-2 antigens, neutralizing antibodies against the reference Wuhan SARS-CoV-2 strain and used SARS-CoV-2 peptides to detect IFN-g and IL-2 specific T cell responses in a group of CoronaVac vaccinated individuals (N = 101) and convalescent (N = 72) individuals. The frequency among vaccinated individuals, of whom 96% displayed T cell and/or antibody responses to SARS-CoV-2, is comparable to 98.5% responses of convalescent individuals. We observed that among vaccinated individuals, men and individuals 55 years or older developed significantly lower anti-RBD, anti-NP and neutralization titers against the Wuhan strain and antigen-induced IL-2 production by T cells. Neutralizing antibody responses for Gamma variant were even lower than for the Wuhan strain. Even though some studies indicated CoronaVac helped reduce mortality among elderly people, considering the appearance of novel variants of concern, CoronaVac vaccinated individuals above 55 years old are likely to benefit from a heterologous third dose/booster vaccine to increase immune response and likely protection.
- MHC Variants Associated With Symptomatic Versus Asymptomatic SARS-CoV-2 Infection in Highly Exposed Individuals(2021) CASTELLI, Erick C.; V, Mateus de Castro; NASLAVSKY, Michel S.; SCLIAR, Marilia O.; SILVA, Nayane S. B.; ANDRADE, Heloisa S.; SOUZA, Andreia S.; PEREIRA, Raphaela N.; CASTRO, Camila F. B.; MENDES-JUNIOR, Celso T.; MEYER, Diogo; NUNES, Kelly; MATOS, Larissa R. B.; SILVA, Monize V. R.; WANG, Jaqueline Y. T.; ESPOSITO, Joyce; CORIA, Vivian R.; BORTOLIN, Raul H.; HIRATA, Mario H.; MAGAWA, Jhosiene Y.; CUNHA-NETO, Edecio; COELHO, Veronica; SANTOS, Keity S.; MARIN, Maria Lucia C.; KALIL, Jorge; MITNE-NETO, Miguel; MACIEL, Rui M. B.; PASSOS-BUENO, Maria Rita; ZATZ, MayanaDespite 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.