Mechanistic analysis of immune communication during respiratory viral infections via the placenta-brain axis

Respiratory viral infections during pregnancy can disrupt maternal immune homeostasis, thereby altering placental function and fetal neurodevelopment through cytokine-mediated immune communication. Accumulating evidence suggests that the placenta functions as an active immunological interface, integrating maternal inflammatory signals and shaping fetal neuroimmune development, supporting the concept of the "placenta-brain axis". This review synthesizes current evidence on the cytokine, chemokine, interferon, and complement networks that mediate maternal-fetal immune communication and examines how these pathways are engaged during infections. It addresses four prevalent RNA respiratory viruses for which evidence is available at one or more biological levels of the placenta-brain axis, namely influenza virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human respiratory syncytial virus (hRSV), and human metapneumovirus (hMPV). We highlight substantial differences in the depth of mechanistic evidence across these pathogens, with influenza virus and SARS-CoV-2 supported by comparatively robust experimental evidence, whereas hRSV and hMPV remain biologically plausible but mechanistically underexplored models of maternal-fetal immune communication. Hence, we propose a framework that grades mechanistic evidence across the placenta-brain axis against four explicit criteria and identify gestational timing, fetal sex, and maternal background inflammation as variables that modulate the transmission of inflammatory signals between levels. This structured approach identifies knowledge gaps and guides future mechanistic and translational research.