Antonio, L. S. | Search bioRxiv

bioRxiv2025

Leishmania amazonensis infection induces IL1β-dependent hyperalgesia, while dampening mechanical allodynia in C57BL/6 mice

Leishmaniases are neglected diseases causing significant deaths and disabilities. In Brazil, the most prevalent form is cutaneous leishmaniasis, characterized by painless lesions despite intense inflammation and ulceration. While BALB/c mice models exhibit hypersensitization to inflammatory stimuli, C57BL/6 mice better mimic human-like lesion progression and nociceptive responses. This study aimed to investigate the mechanisms underlying nociceptive changes in cutaneous leishmaniasis using the C57BL/6 model. Following infection with L. amazonensis, behavioral and nociceptive tests revealed unaltered mechanical nociception and motor capacity, though thermal hypersensitivity emerged during the chronic phase. Elevated IL-1{beta} production in the lesions and upregulation of TRPV1 in dorsal root ganglia (DRG) neurons were detected via ELISA and qPCR. Mice deficient in IL-1{beta}-related proteins or receptors exhibited higher thermal nociception thresholds, highlighting IL-1{beta}s role in heat hypersensitization during late infection stages. Microscopy of chronic lesions revealed tissue deformities, indicating desensitization to mechanical and inflammatory stimuli due to nerve terminal alterations and fibroplasia from regenerative processes. Conversely, thermal hypersensitivity in chronic phases was driven by IL-1{beta} effects on thermal nociceptive neurons in the DRG. These findings suggest that IL-1{beta} and TRPV1 contribute to thermal hypersensitivity, while structural changes in lesions underlie mechanical desensitization. This model provides insights into the complex nociceptive mechanisms of cutaneous leishmaniasis.

pathology↗

bioRxiv2022

SARS-CoV-2 spike protein induces long-term TLR4-mediated synapse and cognitive loss recapitulating Post-COVID syndrome

Cognitive dysfunction is often reported in post-COVID patients, but its underlying mechanisms remain unknown. While some evidence indicate that SARS-CoV-2 can reach and directly impact the brain, others suggest viral neuroinvasion as a rare event. Independently of brain viral infection, the ability of SARS-CoV-2 spike (S) protein to cross the BBB and reach memory-related brain regions has already been shown. Here, we demonstrate that brain infusion of S protein in mice induces late cognitive impairment and increases serum levels of neurofilament light chain (NFL), which recapitulates post-COVID features. Neuroinflammation, hippocampal microgliosis and synapse loss are induced by S protein. Increased engulfment of hippocampal presynaptic terminals late after S protein brain infusion were found to temporally correlate with cognitive deficit in mice. Blockage of TLR4 signaling prevented S-associated detrimental effects on synapse and memory loss. In a cohort of 86 patients recovered from mild COVID-19, genotype GG TLR4 -2604G>A (rs10759931) was associated with poor cognitive outcome. Collectively, these findings indicate that S protein directly impacts the brain and suggest that TLR4 is a potential target to prevent post-COVID cognitive dysfunction. One Sentence SummaryTLR4 mediates long-term cognitive impairment in mice and its genetic variant increases the risk of poor cognitive outcome in post-COVID patients.

neuroscience↗