Biology subjects

McIntire, K. M.

Publications and source records attributed to McIntire, K. M..

6 recordsLinked to original sources

bioRxiv2024

CD28 Shapes T Cell Receptor Signaling by Regulating ZAP70 Activation and Lck Dynamics

T cell activation requires T cell receptor (TCR) engagement, which initiates a series of proximal events including tyrosine phosphorylation of the CD3 and TCR{zeta} chains, recruitment, and activation of the protein tyrosine kinases Lck and ZAP70, followed by recruitment of adapter and signaling proteins. CD28 co-stimulation is also required to generate a functional immune response. Currently we lack a full understanding of the molecular mechanism of CD28 activation. TCR microclusters (MC) are submicron-sized molecular condensates and basic signaling units that form immediately after TCR ligation. Our results show that CD28 co-stimulation specifically accelerated recruitment of ZAP70 to the TCR{zeta} chain in MCs and increased ZAP70 activation. This CD28-mediated acceleration of ZAP70 recruitment was driven by enhanced Lck recruitment to the MCs. A greater spatial separation between active and inactive species of Lck was also observed in the MCs as a consequence of CD28 co-stimulation. These results suggest that CD28 co-stimulation may lower the TCR activation threshold by enhancing the activated form of Lck in the TCR MCs.

immunology↗

bioRxiv2024

Microsporidian coinfection reduces fitness of a fungal pathogen due to rapid host mortality

Infection outcomes can be strongly context-dependent, shifting a host-symbiont relationship along a parasitism-mutualism continuum. Numerous studies show that under stressful conditions, symbionts that are typically mutualistic can become parasitic. The reverse possibility - a parasite becoming mutualistic - has received much less study. We investigated whether the parasitic microsporidium Ordospora pajunii can become beneficial for its host Daphnia dentifera in the presence of the more virulent fungal pathogen Metschnikowia bicuspidata. We found that, even though infection with O. pajunii reduces the frequency of penetration of M. bicuspidata spores into the host body cavity, it does not improve the survival or reproduction of the host; conversely, coinfection increased the mortality of Daphnia. However, the shorter lifespan of coinfected hosts disrupted the life cycle of M. bicuspidata, greatly reducing its fitness. Thus, coinfection with both pathogens was detrimental to the host at the individual level, but might be beneficial for the host population as a result of greatly reduced production of M. bicuspidata spores. If so, this would mean that O. pajunii outbreaks should delay or prevent M. bicuspidata outbreaks. In support of this, in an analysis of dynamics of naturally occurring outbreaks in two lakes where these pathogens co-occur, we found a time lag in occurrence between O. pajunii and M. bicuspidata, with M. bicuspidata epidemics only occurring after the collapse of O. pajunii epidemics. Thus, these results suggest that the interaction between co-occurring symbionts - and the net impact of a symbiont on a host - might be qualitatively different at different scales. ImportanceUnderstanding the factors that modify infection probability and virulence is crucial for identifying the drivers of infection outbreaks and modeling disease epidemic progression, and increases our ability to control diseases and reduce the harm they cause. One factor that can strongly influence infection probability and virulence is the presence of other pathogens. However, while coexposures and coinfections are incredibly common, we still have only a limited understanding of how pathogen interactions alter infection outcomes, or whether their impacts are scale-dependent. We used a system of one host and two pathogens to show that sequential coinfection can have a tremendous impact on the host and on the infecting pathogens, and that the outcome of (co-)infection can be negative or positive depending on the focal organization level.

ecology↗

bioRxiv2023

Spatiotemporal development of the human T follicular helper cell response to Influenza vaccination

We profiled blood and draining lymph node (LN) samples from human volunteers after influenza vaccination over two years to define evolution in the T follicular helper cell (TFH) response. We show LN TFH cells expanded in a clonal-manner during the first two weeks after vaccination and persisted within the LN for up to six months. LN and circulating TFH (cTFH) clonotypes overlapped but had distinct kinetics. LN TFH cell phenotypes were heterogeneous and mutable, first differentiating into pre-TFH during the month after vaccination before maturing into GC and IL-10+ TFH cells. TFH expansion, upregulation of glucose metabolism, and redifferentiation into GC TFH cells occurred with faster kinetics after re-vaccination in the second year. We identified several influenza-specific TFH clonal lineages, including multiple responses targeting internal influenza proteins, and show each TFH state is attainable within a lineage. This study demonstrates that human TFH cells form a durable and dynamic multi-tissue network.

immunology↗

bioRxiv2023

Phylogeny, morphology, virulence, ecology, and host range of Ordospora pajunii (Ordosporidae),a microsporidian symbiont of Daphnia spp.

Impacts of microsporidia on host individuals are frequently subtle and can be context dependent. A key example of the latter comes from a recently discovered microsporidian symbiont of Daphnia, the net impact of which was found to shift from negative to positive based on environmental context. Given this, we hypothesized low baseline virulence of the microsporidian; here, we investigated the impact of infection on hosts in controlled conditions and the absence of other stressors. We also investigated its phylogenetic position, ecology and host range. The genetic data indicates that the symbiont is Ordospora pajunii, a newly described microsporidian parasite of Daphnia. We show that O. pajunii infection damages the gut, causing infected epithelial cells to lose microvilli and then rupture. The prevalence of this microsporidian could be high (up to 100% in the lab and 77% of adults in the field). Its overall virulence was low in most cases, but some genotypes suffered reduced survival and/or reproduction. Susceptibility and virulence were strongly host-genotype dependent. We found that North American O. pajunii were able to infect multiple Daphnia species, including the European species D. longispina, as well as Ceriodaphnia spp. Given the low, often undetectable virulence of this microsporidian, and potentially far reaching consequences of infections for the host when interacting with other pathogens or food, this Daphnia - O. pajunii symbiosis emerges as a valuable system for studying the mechanisms of context-dependent shifts between mutualism and parasitism, as well as for understanding how symbionts might alter host interactions with resources. ImportanceThe net outcome of symbiosis depends on the costs and benefits to each partner. Those can be context dependent, driving the potential for an interaction to change between parasitism and mutualism. Understanding the baseline fitness impact in an interaction can help us understand those shifts; for an organism that is generally parasitic, it should be easier for it to become a mutualist if its baseline virulence is relatively low. Recently, a microsporidian was found to become beneficial to its Daphnia hosts in certain ecological contexts, but little was known about the symbiont (including its species identity). Here, we identify it as the microsporidium Ordospora pajunii. Despite the parasitic nature of microsporidia, we found O. pajunii to be, at most, mildly virulent; this helps explain why it can shift towards mutualism in certain ecological contexts and helps establish O. pajunii is a valuable model for investigating shifts along the mutualism-parasitism continuum.

ecology↗

bioRxiv2023

Transgenerational virulence: Maternal pathogen exposure reduces offspring fitness

Pathogens can alter the phenotype not only of exposed hosts, but also of future generations. Transgenerational immune priming, where parental infection drives reduced susceptibility of offspring, has been particularly well explored, but pathogens can also alter life history traits of offspring. Here, we examined the potential for transgenerational impacts of a microsporidian pathogen, Ordospora pajunii, by experimentally measuring the impact of maternal exposure on offspring fitness in the presence and absence of parasites, and then developing mathematical models that explored the population-level impacts of these transgenerational effects. We did not find evidence of transgenerational immune priming: offspring of exposed mothers became infected at high rates, similar to offspring of unexposed mothers, and the infection burden did not differ between these two groups. We also did not find any evidence of transgenerational tolerance, where daughters of exposed mothers have higher fitness after infection. Instead, we found evidence for negative transgenerational impacts of infection: uninfected offspring of exposed mothers had substantially greater early life mortality than uninfected offspring of unexposed mothers. Offspring of exposed mothers also had reduced growth rate, fewer clutches, and fewer offspring. We propose that these observations should be considered transgenerational virulence, where a pathogen reduces the fitness of the offspring of infected hosts. Our parameterized mathematical model allowed us to explore the impacts of transgenerational virulence at the population level. If transgenerational virulence manifests as decreased reproduction or increased mortality in offspring, as we saw in the empirical portion of our study, this reduces total host density, infection prevalence, and infected host density, which could have implications for both host conservation and spillover risk. We propose that transgenerational virulence might be common and is a concept worthy of further empirical and theoretical exploration.

ecology↗

bioRxiv2022

SARS-CoV-2 Omicron boosting induces de novo B cell response in humans

The primary two-dose SARS-CoV-2 mRNA vaccine series are strongly immunogenic in humans, but the emergence of highly infectious variants necessitated additional doses of these vaccines and the development of new variant-derived ones1-4. SARS-CoV-2 booster immunizations in humans primarily recruit pre-existing memory B cells (MBCs)5-9. It remains unclear, however, whether the additional doses induce germinal centre (GC) reactions where reengaged B cells can further mature and whether variant-derived vaccines can elicit responses to novel epitopes specific to such variants. Here, we show that boosting with the original SARS- CoV-2 spike vaccine (mRNA-1273) or a B.1.351/B.1.617.2 (Beta/Delta) bivalent vaccine (mRNA-1273.213) induces robust spike-specific GC B cell responses in humans. The GC response persisted for at least eight weeks, leading to significantly more mutated antigen-specific MBC and bone marrow plasma cell compartments. Interrogation of MBC-derived spike-binding monoclonal antibodies (mAbs) isolated from individuals boosted with either mRNA-1273, mRNA-1273.213, or a monovalent Omicron BA.1-based vaccine (mRNA-1273.529) revealed a striking imprinting effect by the primary vaccination series, with all mAbs (n=769) recognizing the original SARS-CoV-2 spike protein. Nonetheless, using a more targeted approach, we isolated mAbs that recognized the spike protein of the SARS-CoV-2 Omicron (BA.1) but not the original SARS-CoV-2 spike from the mRNA-1273.529 boosted individuals. The latter mAbs were less mutated and recognized novel epitopes within the spike protein, suggesting a naive B cell origin. Thus, SARS-CoV-2 boosting in humans induce robust GC B cell responses, and immunization with an antigenically distant spike can overcome the antigenic imprinting by the primary vaccination series.

immunology↗