Zika virus may not be alone: proteomics associates a bovine-like viral diarrhea virus to microcephaly

Abstract

One Sentence Summary:Proteomics analysis lead us to suspect the presence of a Bovine-like viral diarrhea virus (BVDV-like) in the brain tissue of fetuses bearing microcephaly during the outbreak in Paraíba State, Brazil, 2015. AbstractNo direct experimental causal evidence confirms that the Zika virus is the sole etiological agent responsible for the development of brain malformations in human fetuses during pregnancy. We used a discovery-driven approach to analyze protein extracts of three Zika positive brains. Shotgun mass spectrometry (MS) proteomics did not identify any Zika protein in all samples. However, MS detected the presence of peptide(s) from the polyprotein of a Bovine-like viral diarrhea virus (BVDV-like) in Zika-positive brains. These results indicate that Zika virus may not be, per se, the only etiological agent responsible for microcephaly and suggests that discovery-driven approaches play an essential role in the screening of fluids or tissues for virus or other etiological agents. MAIN TEXTTo the Zika infection in Bahia, Brazil in 2015 (1) followed a dramatic outbreak of microcephaly in the Northeastern Brazilian States of Paraíba, Pernambuco and Bahia (2). In January 2016, Melo suggested a correlation between Zika infection and fetal microcephaly during a two case study of women living in Paraiba State who complained of symptoms of Zika virus infection during pregnancy; real time PCR confirmed the presence of Zika virus in children brain tissue and amniotic fluid (3). Other groups associated the presence of Zika virus to microcephaly (4) and reviewed the evidence for causality by several criteria (5). However, reports linking high incidence of human microcephaly to the presence of Zika virus do not disclose any experimental data that provide a direct link between microcephaly and Zika virus during fetal brain development in spite of reducing viability and growth of neurospheres and brain organoids (6). Here, we expand these findings using discovery-driven shotgun . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/062596 doi: bioRxiv preprint first posted online Jul. 15, 2016; proteomics based on high resolution and accuracy mass spectrometry analysis to show the detection of a BVDV-like virus in tissue extracts of Zika positive brains. Microcephaly is associated with genetic disorders. Among others, chromosomal trisomy (Edward´s), Aicardi-Goutieres´ and Rett´s syndromes and X-chromosomal microcephaly and trans-placental infections by viruses or bacteria, including rubella, cytomegalovirus, herpes simplex, varicella zoster virus, HIV, arboviruses and maternal malnutrition or drug use and chemical intoxication of pregnant mothers (3-5, 7).Reports disclosed the incidence of Central Nervous System (CNS) malformations in fetuses and neonates after the Zika virus outbreak in French Polynesia; however, incidence of microcephaly associated with the outbreak was n...

Gross Motor Function in Children with Congenital Zika Syndrome

“…4,10,33 An unprecedented association between lower economic level and severe motor function was observed. Recent studies have shown that low yellow fever vaccination coverage 34 and previous infections by viruses or other etiologic agents, 35 factors to which lower socioeconomic classes are more exposed, can increase the severity of neurological involvement in congenital ZIKV infection. Moreover, CZS results in high-magnitude disabilities or difficulties in function and body structure, activity, and participation in daily life activities, 36 creating several demands that are potentially difficult to meet in families with low socioeconomic status.…”

Serological survey on Bovine viral diarrhea virus in man and evaluation of relation with Zika virus associated microcephaly

“…Research teams from the Federal University of Rio de Janeiro and the research Institute Professor Joaquim Amorim Neto, Campina Grande, identified BVD virus (BVDV) in fetal samples with microcephaly, originating in the state of Paraíba ( Nogueira et al ., 2016 ). Two virus sequences obtained from the amniotic fluid collected from mothers with babies affected by Zika and microcephaly have been characterized as BVDV, according to secondary structure analysis ( Giangaspero and Apicella, 2018 ).…”

Zika Virus-Bovine Viral Diarrhea Virus Potential Interaction in the Etiopathology of Birth Defects in Brazil, a One Health Issue?

“…Research teams from the Federal University of Rio de Janeiro and Instituto de Pesquisa Professor Joaquim Amorim Neto, Campina Grande, identified Bovine Viral Diarrhea Virus (BVDV) in fetal samples with microcephaly, originating in the state of Paraíba. Using mass spectrometry proteomics to analyze protein extracts from three Zika positive brains of deceased babies with severe brain lesions and arthrogryposis, Nogueira and others detected the presence of peptides from the poly-protein of a Bovine-like viral diarrhea virus, suggesting that Zika virus may not be the only etiological agent responsible for microcephaly [10]. Melo and her team suggested that Zika infection might facilitate BVDV to cross placenta barrier and cause fetal infections; however, they haven't ruled out the possibility that their findings might be due to contamination [11].…”

“…Despite there is general consensus on the correlation of Zika virus with microcephaly [23], no direct experimental causal evidence confirms that the Zika virus is the sole etiological agent responsible for the development of brain malformations in human fetuses during pregnancy [10]. The zoonotic potential of BVDV, its ability to cross species barrier, to cross hemato-placental barrier, the high tropism for CNS in animal fetuses, as well as the synergistic action with other pathogens trough the virus induced transient but severe immune-depression, suggest this virus as cofactor candidate for eventual interaction with Zika virus in the etiopathogenesis of CNS lesions induced in human in epidemic areas of South America.…”