AUTHOR=Schmitt Kimberly , Curlin James Z. , Remling-Mulder Leila , Aboellail Tawfik , Akkina Ramesh 

TITLE=Zika virus induced microcephaly and aberrant hematopoietic cell differentiation modeled in novel neonatal humanized mice

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1060959

DOI=10.3389/fimmu.2023.1060959

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Immunocompetent and immunocompromised murine models have been instrumental in answering important questions regarding ZIKV pathogenesis and vertical transmission. However, mimicking human congenital zika syndrome (CZS) characteristics in these murine models has been less than optimal and does not address the potential viral effects on the human immune system.</p></sec><sec><title>Methods</title><p>Here, we utilized neonatal humanized Rag2<sup>-/-</sup>γc<sup>-/-</sup> mice to model CZS and evaluate the potential viral effects on the differentiation of human hematopoietic stem cells <italic>in vivo</italic>. Newborn Rag2<sup>-/-</sup>γc<sup>-/-</sup> mice were engrafted with ZIKV-infected hematopoietic stem cells (HSC) and monitored for symptoms and lesions.</p></sec><sec><title>Results</title><p>Within 13 days, mice displayed outward clinical symptoms that encompassed stunted growth, hunched posture, ruffled fur, and ocular defects. Striking gross pathologies in the brain and visceral organs were noted. Our results also confirmed that ZIKV actively infected human CD34<sup>+</sup> hematopoietic stem cells and restricted the development of terminally differentiated B cells. Histologically, there was multifocal mineralization in several different regions of the brain together with ZIKV antigen co-localization. Diffuse necrosis of pyramidal neurons was seen with collapse of the hippocampal formation.</p></sec><sec><title>Discussion</title><p>Overall, this model recapitulated ZIKV microcephaly and CZS together with viral adverse effects on the human immune cell ontogeny thus providing a unique <italic>in vivo</italic> model to assess the efficacy of novel therapeutics and immune interventions.</p></sec>