Several studies have considered that Sertoli cells are a key target for ZIKV infection in the testes [59,62,64]. Additionally, antiviral treatment with AH-D peptide may be beneficial during early maternal ZIKV infection. Fund This work was supported by the Brazilian National Science Council (CNPq, Brazil), Minas Gerais Foundation for Science (FAPEMIG), Funding Authority for Studies and Projects (FINEP), Coordination of Superior Level Staff Improvement (CAPES), National Clindamycin Phosphate Research Foundation of Singapore and Centre for Precision Biology at Nanyang Technological University. infection (CZI), Congenital Zika Syndrome (CZS), Maternal immune activation Clindamycin Phosphate (MIA), Antibody-dependent enhancement (ADE), Short and long-term outcomes Research in context Evidence before this study It is known that (ZIKV) infection during pregnancy can cause several birth defects to developing foetuses, and this disease state is termed Congenital Zika Syndrome (CZS). However, few studies have begun to investigate the potential long-term outcomes of affected offspring and Clindamycin Phosphate possible pathogenic mechanisms. In addition, maternal immune activation (MIA) during pregnancy is associated with the development of neuropsychiatric diseases of offspring during adulthood. Thus, consequences of congenital ZIKV infection might not only be caused by pathological effects of the virus infection, but also due to maternal inflammatory mechanisms. Finally, a novel antiviral peptide called AH-D showed therapeutic activity against ZIKV in vivo. Therefore, the IkBKA peptide’s antiviral activity should be further tested in other pre-clinical models to evaluate its potential therapeutic use. Added value of this study Here, we demonstrated that ZIKV infection in immunocompetent mice induced relevant maternal and foetal abnormalities, which worsened in the presence of anti-flavivirus antibodies. During the post-natal period, several alterations in the offspring of ZIKV-infected dams were detected, some of which were enhanced by previous flavivirus immunity and affected several systems such as the brain, eyes, testes, and bones. Finally, we provided further evidence that AH-D peptide therapy can abrogate ZIKV replication in vivo during pregnancy and ameliorated foetal abnormalities caused by ZIKV infection. Implications of all the available evidence Our findings highlight several short- and long-term consequences of congenital ZIKV infection, which could be potential clinical outcomes that might be expected in individuals born from ZIKV-infected mothers, and finally support the feasibility of an antiviral peptide therapy to prevent adverse pregnancy outcomes induced by ZIKV infection. Taken together, the current results suggest that the general population and clinicians should remain vigilant of long-term, potentially harmful symptoms that may afflict apparently healthy children who were born from ZIKV-infected mothers. Alt-text: Unlabelled Box 1.?Introduction (ZIKV) infection emerged as a global public health threat that is associated with severe neurological complications. ZIKV is an arbovirus that belongs to the family and is mainly transmitted to humans through the bite of infected mosquitoes. Vertical transmission in humans can result in early miscarriage or mild to severe birth defects, which include visual and hearing impairment . The most severe outcome after congenital ZIKV infection (CZI) is severe microcephaly and the long-term consequences of ZIKV infection has yet to be determined. The term Congenital Zika Syndrome (CZS) has been coined to describe the most significant and pathognomonic alterations observed after ZIKV infection of the foetus: microcephaly and one or more other complications, including vision and hearing impairment, as well as articular and musculoskeletal abnormalities [2,3]. Epidemiological and experimental studies.