Biology subjects

Kelvin, D. J.

Publications and source records attributed to Kelvin, D. J..

3 recordsLinked to original sources

bioRxiv2025

MPXV Clade IIb virus infection in mice leads to prolonged viral replication, macrophage infiltration, and decreased spermatogenesis in the testes.

Mpox (formerly monkeypox) is caused by monkeypox virus (MPXV) and has prompted two recent global health emergencies. Clade IIb MPXV, a recently recognized subclade, has been associated with oral and genital lesions and transmission among men who have sex with men (MSM); however, mechanisms of genital pathogenesis and sexual transmission are not understood. We investigated several routes of MPXV Clade IIb virus infection (intranasal, oral, anal, and intraperitoneal) and found high and prolonged viral titres in the testes after IP inoculation still detectable at 21 days. The testes had significant changes to tissue architecture including loss of spermatogenesis, disorganization of spermatozoa, loss of Leydig cells, and breakdown of the seminiferous tubule membranes. Viral antigen positive cells were present in the interstitial spaces between the seminiferous tubules with macrophage infiltration also evident. This work provides insights into potential of sexual transmission for MPXV viruses as well as mechanisms of Mpox disease which may significantly impact long-term fertility or sex organ health of infected males. Author SummaryMpox (formerly monkeypox) is a painful disease similar to smallpox caused by the monkeypox virus (MPXV) which is an emerging/re-emerging virus. Recently the WHO has declared two global health emergencies due to human-to-human transmission of MPXV. Clade IIb MPXV is a newly recognized subclade that has been associated with genital lesions and sexual transmission/contact; however, how the virus causes disease in sex-organs or how it is passed from person-to-person is not understood. We investigated several routes of MPXV Clade IIb inoculation and found IP inoculation in male mice led to high and prolonged viral titres in testes. Additionally, the testes were significantly affected having loss of sperm and cellular organization. Evidence of inflammatory cell infiltration, specifically, macrophages, are suspected to be the cause of testes specific disease. This work provides insights into potential of sexual transmission for MPXV viruses as well as mechanisms of Mpox disease.

microbiology↗

bioRxiv2018

Cross-protective immune responses induced by sequential influenza virus infection and by sequential vaccination with inactivated influenza vaccines

Sequential infection with antigenically distinct influenza viruses induces cross-protective immune responses against heterologous virus strains in animal models. Here we investigated whether sequential immunization with antigenically distinct influenza vaccines can also provide cross-protection. To this end, we compared immune responses and protective potential against challenge with A(H1N1)pdm09 in mice infected sequentially with seasonal A(H1N1) virus followed by A(H3N2) virus or immunized sequentially with whole inactivated virus (WIV) or subunit (SU) vaccine derived from these viruses. Sequential infection provided solid cross-protection against A(H1N1)pdm09 infection while sequential vaccination with WIV, though not capable of preventing weight loss upon infection completely, protected the mice from reaching the humane endpoint. In contrast, sequential SU vaccination did not prevent rapid and extensive weight loss. Protection correlated with levels of cross-reactive but non-neutralizing antibodies of the IgG2a subclass, general increase of memory T cells and induction of influenza-specific CD4+ and CD8+ T cells. Adoptive serum transfer experiments revealed that despite lacking neutralizing activity, serum antibodies induced by sequential infection protected mice from weight loss and vigorous virus growth in the lungs upon A(H1N1)pdm09 virus challenge. Antibodies induced by WIV vaccination alleviated symptoms but could not control virus growth in the lung. Depletion of T cells prior to challenge revealed that CD8+ T cells, but not CD4+ T cells, contributed to cross-protection. These results imply that sequential immunization with WIV but not SU derived from antigenically distinct viruses could alleviate the severity of infection caused by a pandemic and may improve protection to unpredictable seasonal infection.\n\nImportanceNew influenza virus strains entering the human population may have large impact and therefore their emergence requires immediate action. Yet, since these strains are unpredictable, vaccines cannot be prepared in advance, at least not as long as there is no universal or broadly protective influenza vaccine available. It is therefore important to elucidate in how far immunization strategies based on currently available seasonal vaccines can provide at least some protection against newly emerging virus strains. Moreover, insight in the possible mechanisms of protection can guide the further development of pre-pandemic immunization strategies. Our study presents a vaccination strategy based on sequential administration of readily available seasonal whole inactivated virus vaccines which could be easily applied in case of a new pandemic. In addition, our study identifies immune mechanisms, in particular cross-reactive non-neutralizing antibodies and CD8+ T cells, which should be targeted by broadly protective influenza vaccines.

microbiology↗

bioRxiv2017

Novel insights into the molecular heterogeneity of hepatocellularcarcinoma

Hepatocellular carcinoma (HCC) is influenced by numerous factors, which results in diverse genetic, epigenetic and transcriptional scenarios, thus posing obvious challenges for disease management. We scrutinized the molecular heterogeneity of HCC with a multi-omics approach in two small cohorts of resected and explanted livers. Whole-genome transcriptomics was conducted, including polyadenylated transcripts and micro (mi)-RNAs. Copy number variants (CNV) were inferred from whole genome low-pass sequencing data. Fifty-six cancer-related genes were screened using an oncology panel assay. HCC was associated with a dramatic transcriptional deregulation of hundreds of protein-coding genes suggesting downregulation of drugs catabolism, induction of inflammatory responses, and increased cell proliferation in resected livers. Moreover, several long non-coding RNAs and miRNAs not reported previously in the context of HCC were found deregulated. In explanted livers, downregulation of genes involved in energy-producing processes and upregulation of genes aiding in glycolysis were detected. Numerous CNV events were observed, with conspicuous hotspots on chromosomes 1 and 17. Amplifications were more common than deletions, and spanned regions containing genes potentially involved in tumorigenesis. CSF1R, FGFR3, FLT3, NPM1, PDGFRA, PTEN, SMO and TP53 were mutated in all tumors, while other 26 cancer-related genes were mutated with variable penetrance. Our results highlight a remarkable molecular heterogeneity between HCC tumors and reinforce the notion that precision medicine approaches are urgently needed for cancer treatment. We expect that our results will serve as a valuable dataset that will generate hypotheses for us or other researchers to evaluate to ultimately improve our understanding of HCC biology.

cancer biology↗