Immunological imbalance in microcephalic children with congenital Zika virus syndrome

Salmeron, Amanda Costa Ayres; Bezerra, Wallace Pitanga; Souza, Rafaela Lúcia Lopes de; Pereira, Luanderson Cardoso; Nascimento, Lícia Maria do; Branco, Anna Cláudia Calvielli Castelo; Simas, Luiza Emilia Cavalcanti; Almeida, Valéria Azevedo de; Palmeira, Pedro Henrique de Souza; Bezerra, Christiane Medeiros; Guedes, Paulo M. M.; Sato, Maria Notomi; Sales, Valéria Soraya de Farias; Júnior, Reginaldo Antônio de Oliveira Freitas; Keesen, Tatjana Souza Lima; Nascimento, Manuela Sales Lima

doi:10.1007/s00430-022-00746-5

Cited by 3 publications

(17 citation statements)

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“…Considering the previously described elevation of IL-2, IL-4, IL-5, and IFNγ in the serum of children with CZS, accompanied by peripheral blood eosinophilia [ 6 ], we aimed to evaluate the expression of other mediators that could be related to this inflammatory imbalance. We performed qPCR using total blood samples from individuals in both study groups, assessing the expression of type II and III interferons, ISG15 (antiviral and inflammatory response), IL-13 and MMP9 (Th2 profile and eosinophilic activity marker), RORγt (Th17 profile), AXL and CD209 (ZIKV entry receptors), and TGF-β, FoxP3, and IL-10 (anti-inflammatory response) ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to direct consequences on the central nervous system (CNS), such as developmental delay and visual and auditory impairments, other organs and systems sequelae have been described in children with microcephaly due to congenital infections, such as calcifications in the liver, spleen, and thymus; arthrogryposis; muscular hypertonia; visual and auditory problems; cardiomegaly and diaphragmatic paralysis [ 3 , 4 , 5 , 6 , 7 ]. This occurs because disruption of homeostasis triggered by intrauterine infection affects the proper development and maturation of various fetal tissues, with consequences often defined by the timing of infection during pregnancy and the pathogen involved [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, studies describing inflammatory changes in the peripheral blood of children with CZS have predominantly focused on neonates, and it is unclear whether this imbalance persists throughout childhood. With this in mind, our group has previously identified significant morphometric alterations in the thymus and spleen of children with microcephaly due to CZS using ultrasound [ 6 ]. Additionally, we observed leukocyte morphological changes, eosinophilia, and increased serum levels of IL-2, IL-4, IL-5, and type I and II interferons.…”

Section: Introductionmentioning

confidence: 99%

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Low CCL2 and CXCL8 Production and High Prevalence of Allergies in Children with Microcephaly Due to Congenital Zika Syndrome

Bezerra,

Salmeron,

Branco

et al. 2023

Viruses

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Congenital Zika Syndrome (CZS) is associated with an increased risk of microcephaly in affected children. This study investigated the peripheral dysregulation of immune mediators in children with microcephaly due to CZS. Gene expression quantified by qPCR in whole blood samples showed an increase in IFNγ and IL-13 transcripts in children affected with microcephaly compared to the control group. The microcephaly group exhibited significantly decreased CCL2 and CXCL8 levels in serum, quantified by CBA assay. An allergic profile questionnaire revealed a high prevalence of allergies in the microcephaly group. In accordance, elevated serum IgE level measured by the Proquantum Immunoassay was observed in children affected with microcephaly compared to the control group. Altogether, these findings show a persistent systemic inflammation in children with microcephaly due to CZS and suggest a possible impairment in leukocyte migration caused by low production of CCL2 and CXCL8, in addition to high levels of IgE associated with high prevalence of allergies. The dysregulation of inflammatory genes and chemokines underscores the importance of understanding the immunological characteristics of CZS. Further investigation into the long-term consequences of systemic inflammation in these children is crucial for developing appropriate therapeutic strategies and tailored vaccination protocols.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Low CCL2 and CXCL8 Production and High Prevalence of Allergies in Children with Microcephaly Due to Congenital Zika Syndrome

Bezerra,

Salmeron,

Branco

et al. 2023

Viruses

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“…Regarding vaccination of CZS children, to date, there are no specific guideline for vaccination and there are few studies published about their immune response to vaccines. The group of Salmeron et al reported that CZS children showed low tuberculin skin test reactivity after 2 years of BCG vaccination ( 11 ). Much like the notion of low tuberculin skin test reactivity in CZS, this response may also translate into other impaired vaccine responses.…”

Section: Discussionmentioning

confidence: 99%

“…Based on this finding, we wondered whether these children would also have low antibody detection to other antigens unrelated to ZIKV. Salmeron et al have shown that children with CZS react poorly to the tuberculin skin test, 2 years after BCG vaccination ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Serological investigation of vaccine-induced antibodies for measles, rubella, and yellow fever viruses in children vertically exposed to Zika virus or with down syndrome

Familiar-Macedo,

Dias,

Carvalho

et al. 2023

Front. Pediatr.

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BackgroundVaccination schedules, as well as their effectiveness and contraindications, need to be evaluated regularly, especially in specific situations. Congenital Zika Syndrome (CZS) is a severe condition that results in extensive functional and neurological impairment of fetuses and newborns due to Zika virus tropism for fetal neural progenitor cells. Down Syndrome (DS) is the leading genetic cause of intellectual disability. The immune impairment in DS has already been described, but little is known about the immune response of CZS children. Thus, CZS and DS are specific conditions that can be considered for a reassessment of the available immunizations. Here, we carried out serological analyses of attenuated vaccines-induced antibodies for measles, rubella, and yellow fever viruses in children aged 2–7, grouped into asymptomatic controls, DS children, and CZS children.MethodsPlasma samples were taken, and vaccination records were compiled during clinical follow-up. Enzymatic immunoassays for quantifying anti-measles and anti-rubella IgG were performed to assess the response to the Measles, Mumps, and Rubella (MMR) vaccine. Plaque Reduction Neutralization Test (PRNT) was performed to investigate neutralizing antibodies in response to the Brazilian vaccine strain of yellow fever (YF-17DD).ResultsWe highlight similar levels of anti-measles IgG and neutralizing antibodies for YF-17DD among CZS, DS, and asymptomatic children, although low positivity of measles data was seen in the three groups. In DS children, the 2–4-year-old group had an increased level of anti-measles IgG compared to the older group of children aged five to seven years. Lower anti-rubella IgG levels were observed in CZS and DS children compared to asymptomatic children. For anti-rubella IgG, the good performance of vaccination in asymptomatic children is due to younger ones rather than older ones.ConclusionsThere were no reports of adverse events after the use of the MMR and YF-17DD indicating that CZS and DS could continue to receive these vaccines, but our data draws attention to the necessity of monitoring the vaccination response in CZS and DS children over time and the possible need to adhere to national measles vaccination campaigns. Scientific research needs to continue to help develop appropriate CZS and DS health guidelines.

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Analysis of congenital Zika syndrome clinicopathologic findings reported in the 8 years since the Brazilian outbreak

Shah,

Mua

et al. 2024

Explor Neuroprot Ther

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Aim: A Zika virus outbreak that began in Brazil, developed into an international public health emergency that extended from February 2015 until November 2016. Zika-infected pregnant women gave birth to a cohort of infants with congenital Zika syndrome (CZS) originally defined by severe microcephaly, retinal scarring, joint deformities, and hypertonia. This study examines the nature, extent, and severity of all CZS clinicopathologic findings described to date, compiled and analyzed by system. It reviews studies monitoring disease progression and proposing classification schemes for CZS stages. The teratogenic cellular and molecular mechanisms implicated in CZS pathogenesis are also discussed. Methods: A systematic review was conducted by literature search through WorldCat.org and ProQuest Central databases to identify studies on case series from the 2015–2016 CZS outbreak. Results: Twenty-six reports were included describing radiologic, ophthalmologic, audiologic, orthopedic, and laboratory test results in CZS cases including stillborns between 2016 and 2023. CZS neuropathology included prenatal and postnatal microcephaly, cerebral calcifications, quadriparesis, epilepsy, ventriculomegaly, reduced cerebral parenchyma, malformation of cortical development, and sleep electroencephalogram disturbances. Visual deficits were due to retinal and optic nerve lesions. Conductive and sensorineural hearing deficits were stable. Hypertonia, hypotonia, and spasticity with foot, hip, knee, and shoulder deformities resulted in arthrogryposis and restricted joint mobility. There was enlargement of immune organs, increased leukocyte counts, and cytokine dysregulation. Oro-craniofacial deformities affected the midface and caused dental eruption delay. Additional studies proposed that these systemic teratogenic effects could be attributable to transplacental Zika virus infection of multiple fetal progenitor cell lineages. Conclusions: The CZS-associated impairments in brain, eye, musculoskeletal, and immunologic functions caused disabilities that varied from moderate to severe, and significantly increased age-specific mortality rates. Further research is warranted to assess progression, classify stages, elucidate the precise molecular mechanisms mediating Zika teratogenicity, develop suitable therapeutic strategies, and design supportive social policies.

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Immunological imbalance in microcephalic children with congenital Zika virus syndrome

Cited by 3 publications

References 47 publications

Low CCL2 and CXCL8 Production and High Prevalence of Allergies in Children with Microcephaly Due to Congenital Zika Syndrome

Low CCL2 and CXCL8 Production and High Prevalence of Allergies in Children with Microcephaly Due to Congenital Zika Syndrome

Serological investigation of vaccine-induced antibodies for measles, rubella, and yellow fever viruses in children vertically exposed to Zika virus or with down syndrome

Analysis of congenital Zika syndrome clinicopathologic findings reported in the 8 years since the Brazilian outbreak

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