Biology subjects

Keesler, R.

Publications and source records attributed to Keesler, R..

5 recordsLinked to original sources

bioRxiv2021

Familial thyroid follicular cell carcinomas in a large number of Dutch German longhaired pointers

Thyroid carcinomas originating from follicular cells of the thyroid gland occur in both humans and dogs and they have highly similar histomorphologic patterns. In dogs, thyroid carcinomas have not been extensively investigated, especially concerning the familial origin of thyroid carcinomas. Here we report familial thyroid follicular cell carcinomas confirmed by histology in 54 Dutch origin German longhaired pointers. From the pedigree, 45 of 54 histopathologically confirmed cases are closely related to a pair of first-half cousins in the past, indicating a familial disease. In addition, genetics contributed more to the thyroid follicular cell carcinoma than other factors by an estimated heritability of 0.62 based on pedigree. The age of diagnosis ranged between 4.5 and 13.5 years, and 76% of cases were diagnosed before 10 years of age, implying an early onset of disease. We observed a significant higher pedigree-based inbreeding coefficient in the affected dogs (mean F 0.23) compared to unaffected dogs (mean F 0.14), suggesting the contribution of inbreeding to tumour development. The unique occurrence of familial thyroid follicular cell carcinoma in this dog population and the large number of affected dogs make this population an important model to identify the genetic basis of familial thyroid follicular cell carcinoma in this breed and may contribute to the research into pathogenesis, prevention and treatment in humans.

cancer biology↗

bioRxiv2020

Neuroanatomical abnormalities in a nonhuman primate model of congenital Zika virus infection

Zika virus (ZIKV) infection of pregnant women can cause major congenital neuronal abnormalities. In the present study, we evaluated neuropathological consequences of fetal ZIKV exposure in rhesus macaques, a highly translatable animal model for human neural development. Quantitative neuroanatomical analyses of the nearly full-term brains of fetuses infected with ZIKV at gestational days 50, 64, and 90, and three procedure-matched sham-inoculated controls were carried out. Whole tissue sections across a complete cerebral hemisphere were evaluated using immunohistochemical and neuroanatomical staining techniques to detect virus localization, identify affected cell types and evaluate gross neuroanatomical abnormalities. None of the subjects were microcephalic. Immunohistochemical staining revealed the presence of ZIKV in the frontal lobe, which contained activated microglia and showed increased apoptosis of immature neurons. ZIKV-infected animals exhibited macrostructural changes within the occipital lobe, including a reduction in gyrification as well as a higher proportion of white matter. Finally, the ZIKV-infected subjects had abnormalities throughout the visual pathway, including disorganization within the lateral geniculate nucleus (LGN) and primary visual cortex (V1). Regional differences tracked with the temporal patterns of the developing brain and likely reflect the neural progenitor cell tropism ZIKV exhibits - painting a picture of inflammatory processes related to viral infiltration sweeping through the cortex, followed by a wave of cell death resulting in morphological changes. These findings may help explain why some infants born with normal sized heads during the ZIKV epidemic manifest developmental challenges as they age, and ultimately may contribute to developing effective treatments and interventions. One sentence summaryMacaque fetuses infected with Zika virus show both macro- and micro-scale neuropathological abnormalities, including decreased gyrencephality, relative increases in cortical white matter, activation of glia, and increased apoptosis.

neuroscience↗

bioRxiv2020

Two sides of a coin: a Zika virus mutation selected in pregnant rhesus macaques promotes fetal infection in mice but at a cost of reduced fitness in nonpregnant macaques and diminished transmissibility by vectors

Although fetal death is now understood to be a severe outcome of congenital Zika syndrome, the role of viral genetics is still unclear. We sequenced Zika virus (ZIKV) from a rhesus macaque fetus that died after inoculation and identified a single intra-host mutation, M1404I, in the ZIKV polyprotein, located in NS2B. Targeted sequencing flanking position 1404 in 9 additional macaque mothers and their fetuses identified M1404I at sub-consensus frequency in the majority (5 of 9, 56%) of animals and some of their fetuses. Despite its repeated presence in pregnant macaques, M1404I occurs rarely in humans since 2015. Since the primary ZIKV transmission cycle is human-mosquito-human, mutations in one host must be retained in the alternate host to be perpetuated. We hypothesized that ZIKV I1404 increases fitness in non-pregnant macaques and pregnant mice but is less efficiently transmitted by vectors, explaining its low frequency in humans during outbreaks. By examining competitive fitness relative to M1404, we observed that I1404 produced lower viremias in non-pregnant macaques and was a weaker competitor in tissues. In pregnant wildtype mice ZIKV I1404 increased the magnitude and rate of placental infection and conferred fetal infection, contrasting with M1404, which was not detected in fetuses. Although infection and dissemination rates were not different, Ae. aegypti transmitted ZIKV I1404 more poorly than M1404. Our data highlight the complexity of arbovirus mutation-fitness dynamics, and suggest that intrahost ZIKV mutations capable of augmenting fitness in pregnant vertebrates may not necessarily spread efficiently via mosquitoes during epidemics. IMPORTANCEAlthough Zika virus infection of pregnant women can result in congenital Zika syndrome, the factors that cause the syndrome in some but not all infected mothers are still unclear. We identified a mutation that was present in some ZIKV genomes in experimentally inoculated pregnant rhesus macaques and their fetuses. Although we did not find an association between the presence of the mutation and fetal death, we performed additional studies with it in non-pregnant macaques, pregnant mice, and mosquitoes. We observed that the mutation increased the ability of the virus to infect mouse fetuses but decreased its capacity to produce high levels of virus in the blood of non-pregnant macaques and to be transmitted by mosquitoes. This study shows that mutations in mosquito-borne viruses like ZIKV that increase fitness in pregnant vertebrates may not spread in outbreaks when they compromise transmission via mosquitoes and fitness in non-pregnant hosts.

microbiology↗

bioRxiv2020

Genomic insights into the host specific adaptation of the Pneumocystis genus and emergence of the human pathogen Pneumocystis jirovecii

Pneumocystis jirovecii, the fungal agent of human Pneumocystis pneumonia, is closely related to macaque Pneumocystis. Little is known about other Pneumocystis species in distantly related mammals, none of which are capable of establishing infection in humans. The molecular basis of host specificity in Pneumocystis remains unknown as experiments are limited due to an inability to culture any species in vitro. To explore Pneumocystis evolutionary adaptations, we have sequenced the genomes of species infecting macaques, rabbits, dogs and rats and compared them to available genomes of species infecting humans, mice and rats. Complete whole genome sequence data enables analysis and robust phylogeny, identification of important genetic features of the host adaptation, and estimation of speciation timing relative to the rise of their mammalian hosts. Our data reveals novel insights into the evolution of P. jirovecii, the sole member of the genus able to infect humans.

evolutionary biology↗

bioRxiv2019

Diversity and complexity of the large surface protein family in the compacted genomes of various Pneumocystis species

Pneumocystis, a major opportunistic pathogen in patients with a broad range of immunodeficiencies, contains abundant surface proteins encoded by a multi-copy gene family, termed the major surface glycoprotein (Msg) gene superfamily. This superfamily has been identified in all Pneumocystis species characterized to date, highlighting its important role in Pneumocystis biology. In this report, through a comprehensive and in-depth characterization of 459 msg genes from 7 Pneumocystis species, we demonstrate, for the first time, the phylogeny and evolution of conserved domains in Msg proteins, and provide detailed description of the classification, unique characteristics and phylogenetic relatedness of five Msg families. We further describe the relative expression levels of individual msg families in two rodent Pneumocystis species, the substantial variability of the msg repertoires in P. carinii from laboratory and wild rats, and the distinct features of the expression site for the classic msg genes in Pneumocystis from 8 mammalian host species. Our analysis suggests a wide variety of functions for this superfamily, not only conferring antigenic variation to allow immune evasion but also mediating life-stage development, optimizing cell mobility and adhesion, and adapting to specific host niches or environmental conditions. This study provides a rich source of information that lays the foundation for the continued experimental exploration of the functions of the Msg superfamily in Pneumocystis biology.

molecular biology↗