Biology subjects

Clarke, J. R.

Publications and source records attributed to Clarke, J. R..

4 recordsLinked to original sources

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

Different outcomes of neonatal and adult Zika virus infection on startle reflex and prepulse inhibition in mice

Zika virus (ZIKV) infection causes severe neurological consequences in both gestationally-exposed infants and adults. Sensorial gating deficits strongly correlate to the motor, sensorial and cognitive impairments observed in ZIKV-infected patients. However, to date, no startle response or prepulse inhibition (PPI) assessment has been made in patients or animal models. In this study, we identified different outcomes for the age of infection and sex in wild-type mice: neonatally infected animals presented an increase in PPI and startle latency in both sexes, while adult infected males presented lower startle amplitude but preserved PPI. Our data further the understanding of the functional impacts of ZIKV on the developing and mature nervous system, which could help explain other behavioral and cognitive alterations caused by the virus. With this study, we support the use of startle reflex testing in ZIKV exposed patients, especially infants, allowing for early detection of functional neuromotor damage and early intervention.

neuroscience↗

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↗

bioRxiv2017

Neonatal Zika virus infection causes epileptic seizures, viral persistence and long-term behavioral impairment

A causal relationship between congenital Zika virus (ZIKV) exposure and microcephaly and other neurological disorders have been established, but long-term consequences of infection are still unknown. We evaluated acute and late neuropathological and behavioral consequences of ZIKV infection in a neonatal immunocompetent mouse model. ZIKV showed brain tropism, causing post-natal microcephaly and several behavioral dysfunctions. During the acute phase of infection, mice developed very frequent epileptic seizures, which are consistently reduced by TNF- neutralization. Although adult animals recover from seizures, they become more susceptible to chemically-induced crises. Intriguingly, the virus remained actively replicating in adult animals, which show persistent necrosis and calcifications in the mice brain. Altogether the results reveal late consequences of neonatal ZIKV exposure and suggest the early inhibition of neuroinflammation as a potential treatment.

neuroscience↗