The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by Zika virus

Abstract

31The northeast (NE) region of Brazil commonly goes through drought periods, which 32 favor cyanobacterial blooms, capable of producing neurotoxins with implications for human 33 and animal health. The most severe dry spell in the history of Brazil occurred between 2012 34 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus 35 (ZIKV) outbreak was described in the NE region of Brazil during the same years. In this 36 work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America 37 by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most 38 severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance 39 showed higher cyanobacteria amounts and STX occurrence in human drinking water supplies 40 of NE compared to other regions of Brazil. Experimentally, we described that STX doubled 41 the amount of ZIKV-induced neural cell death in progenitor areas of human brain organoids, 42 while the chronic ingestion of water contaminated with STX before and during gestation 43 caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. 44Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of 45 the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a 46 public health concern regarding the consequences of arbovirus outbreaks happening in areas 47 with droughts and/or frequent freshwater cyanobacterial blooms. 48Author summary 49 The uncontrolled spreading of cyanobacteria in drinking water reservoirs has been the 50 cause of serious public health problems worldwide. Toxin-producing cyanobacterial blooms 51 commonly occur during drought periods in the northeast (NE) region of Brazil. During Zika 52Virus (ZIKV) outbreak in 2015-16, Brazilian NE showed disproportionately higher 53 microcephaly incidence. Here, we test the hypothesis that the cyanotoxin saxitoxin (STX) 54 3 may act as a co-insult for ZIKV. Water quality surveillance data showed increased 55 cyanobacteria population and higher STX amount in NE region during 2014-2018 we observed that neural progenitor cell death was doubled after STX exposure to ZIKV-57 infected brain organoids. In vivo, chronic ingestion of STX during gestational period 58 potentiated ZIKV-derived brain abnormalities in newborn mice. Our study provides new 59 insights that may explain the discrepancies among Brazilian regions regarding CZS severity. 60Moreover, the data highlight the importance of cyanobacteria and cyanotoxin freshwater 61 monitoring for future arbovirus outbreaks. 62

Traditional Knowledge and Use of Rock Pools in the Brazilian Caatinga: Memory and Identity in Temporary Ecosystems

“…The presence of cyanobacteria is especially problematic in Northeastern Brazil as it is the rst place where the association between cyanobacterial blooms and human deaths due to water contamination by cyanotoxins was recorded [50,51]. Cyanobacterial blooms produce cyanotoxins, including saxitoxins, which likely has induced the Congenital Zika Syndrome (ZIKV) [52]. Recently, the ZIKV has emerged as a serious problem in this region, with a high index of microcephaly coinciding with extreme drought periods [52].…”

“…Cyanobacterial blooms produce cyanotoxins, including saxitoxins, which likely has induced the Congenital Zika Syndrome (ZIKV) [52]. Recently, the ZIKV has emerged as a serious problem in this region, with a high index of microcephaly coinciding with extreme drought periods [52].…”

Effects of cyanotoxins in germination, growth and DNA damages of Lettuce sativa (Lettuce) and Coriandrum sativum (Coriander)

“…The experiments were composed by two factors (plants), three treatments (control, microcystin-LR and saxitoxin) with three levels (concentrations) (Figure 1). The microcystin-LR (MC-LR1= 0,4 µg/L; MC-LR2= 1,0 µg/L; MC-LR3= 5,0µg/L) and saxitoxin (SX-1= 0,02µg/L; SX-2= 0,1µg/L; SX-3= 0,4µg/L) concentrations selected for this study were more frequently observed in Brazilian Semiarid water bodies (Moura et al 2018, Pedrosa et al 2020, facilitating the comparison of the laboratorial studies with real case scenarios.Before the experiments, all seeds were sterilized with hypochlorite (0,1%) for 10 min and then washed with Ultra-pure water. Seeds of two plants were placed on double layer of Whatman Nº 1 filter paper as seed beds in petri dishes.…”

“…Neurotoxins are a group of compounds that have clear biological effects on the nervous system but differ in chemical structure and action (Rutkowska et al, 2019). Saxitoxins are found in marine dinoflagellates and freshwater cyanobacteria including Raphidiopsis raciborskii, a common specie in Brazilian water reservoirs (Huang and Zimba, 2019;Pedrosa et al, 2020). Saxtoxins cause VGSC blockage and also prolong gating of potassium channels, however, there are only few studies reported in the literature on the effects of cyanoabacterial saxitoxins on crops and plants (Corbel et al, 2014;Christensen and Khan, 2020).…”

Hypothetical Human Immune Genome Complex Gradient May Help to Explain the Congenital Zika Symdrome Catastrophe in Brazil: A New Theory

“…Similarly, an ecological study found no correlation between the use of the larvicide pyriproxyfen in stored water and microcephaly among municipalities of the metropolitan region of Pernambuco, the epicenter of the Brazilian microcephaly epidemic (Albuquerque et al 2016). Interestingly, experiments in mouse models suggested that maternal diet protein restriction (Barbeito-Andrés et al 2020) and exposure to cyanobacterial saxitoxin through water intake (Pedrosa et al 2019) exacerbate brain malformations induced by ZIKV. In fact, CZS may have multiple environmental cofactors and may be influenced by ZIKV genetic factors, but the constellation of alleles of host genes involved in immune functions may also be important predictor of the occurrence and severity of CZS.…”