**6. Conclusion**

Considering the normal pregnancy, the innate immunity balance is conduct by downregulation of effector T cells and NK cells leading by innate regulatory cells (MDSC) and upregulation of pro-inflammatory cytokines. This innate immune modulation that occurs mainly at the placenta, includes interferon pathway and cell death modulation as shown in **Figure 4A**. Gestation has its own difficulties to successful outcomes regarding maternal immune tolerance. Zika virus infection becomes classified as disease-causing birth defects, developing an abnormal pregnancy, as consequence of immune dysregulation (**Figure 4B**). Thus, antiviral therapy is the key to control this immune imbalance showing positive effects in innate immunity on pregnant mice models. It has been known that efforts through vaccines development targeting pregnant women will be the solution for ZIKV prevention, as well as for other arboviral infections, to maintain immune homeostasis and generate healthy babies. Finally, this chapter brings some new thoughts that help for targeted improvements in medical science considering Zika infection

#### **Figure 4.**

*Summary of innate immunity functionality during normal pregnancy and in Zika virus infection focus on interferon III, myeloid-derived suppressor cells, and programmed cell death activities. During pregnancy, initial signal is dependent on nidation process and placenta formation leading by trophoblasts expansion and activation. Following this process, innate cells, such as neutrophils, DCs, and cytokines are activated (1.A, 2.A) with IL10 and TGF-beta production in periphery, allowing immunosuppressive functionality triggered by regulatory cells (MDSC and Treg) (3.A). This condition facilitates suppression of effector cells (NK and lymphocytes) in peripheral blood and in placenta triggered by MDSC (4.A), whereas Hofbauer cells maintain reactive species (NO) balanced (5.A) as well as the IFN-*λ *downregulation, IFN type I upregulation, and trophoblast autophagy (6.A), contributing to the cross-linking in the fetus-maternal interface. Adding to that, programmed cell death contributes to control the accelerated growth of neural cells in fetus brain (7.A), corroborating with a successful pregnancy. Zika virus has been related to abnormal pregnancy, leading to massive innate immune alteration, causing severe brain damage to fetus. Given that, when the virus is in the blood, there is a gross activation of innate cells, elevation of cytokines and chemokines (1.B, 2.B), and suppressive activity by regulatory cells is compromised (3.B), generating early activation of NK and T cells in blood (4.B) and macrophages in placenta (5.B). Virus invasion in placenta through Hofbauer and trophoblast cells results in high autophagy activity with interferon type I gene highly expressed combined with super downregulation of interferon type III (6.B). This imbalance also contributes to fetal brain damage, orchestra by high activation of apoptosis pathway, avoiding neural cells growing progress. Thus, Zika provides severe damage to fetus, in which drugs, vaccines and immunotherapies have been designed suggesting a modulation of three important keys of innate immunity to control virus replication and spread into fetus-maternal interface: interferon type III expression, MDSC frequency, and autophagy process (highlighted with red rectangles) to avoid severe fetus brain damage, allowing a healthy pregnancy. This figure was made based on the information from Figures 1–3. Figure created using Biorender software (https://www.biorender.com).*

on pregnancy, and innate immune system linked to therapies previewing the prevention and control.
