Histopathological Changes and Immune Response Profile in the Brains of Non-Human Primates Naturally Infected with Yellow Fever Virus

Abstract

In the history of yellow fever (YF) outbreaks in Brazil, howler monkeys (Alouatta sp.) and marmosets (Callithrix sp.) have been among the most affected genera, exhibiting significant hepatic injuries similar to those seen in humans. However, limited information exists regarding yellow fever virus (YFV) infection in their central nervous system (CNS). To address this gap, an epidemiological study was conducted to assess tissue changes, viral detection, and cytokine profiles in the brains of both neotropical primate species when they are naturally infected with YFV. A total of 22 brain samples from these species (8 from Alouatta sp. and 14 from Callithrix sp.) showing infection with YFV in the liver via immunohistochemistry (IHC) were selected. From them, YFV antigen detection occurred in 35.7% (5/14) of Callithrix sp. brain samples and 87.5% (7/8) of Alouatta sp. samples, with a higher frequency of viral antigen quantification in Callithrix sp. Both species exhibited similar CNS lesions, characterized by congestion, low hemorrhage, limited inflammatory infiltration interstitial and perivascular edema associated with neuronal degeneration, neurophagy, and higher cell death (necrosis and apoptosis) quantification. Pro- and anti-inflammatory cytokine profiles were balanced, with TNF-α and IL-1β playing a key role in inflammation, while IL-10 and IL-13 exhibited a prominent role in immunomodulation, suggesting an anti-inflammatory modulation typical of flaviviruses occurs. This study demonstrates that YFV can induce CNS lesions in neotropical primates, establishing it as a secondary target of viral tropism. These findings highlight the importance of collecting nervous tissue during epizootics, particularly in Callithrix sp., as such tissue is often overlooked despite its critical role in disease monitoring.