Biology subjects

Reese, T. A.

Publications and source records attributed to Reese, T. A..

8 recordsLinked to original sources

bioRxiv2026

FXR2 Promotes Autophagic Clearance of Sindbis Virus Capsid and Protects Against Viral Encephalitis

Autophagy protects neurons from viral infection by removing toxic viral components, but the host factors that recognize viral proteins and direct their clearance remain incompletely defined. Here, we identify fragile X mental retardation syndrome-related protein 2 (FXR2) as a mediator of protective autophagy during Sindbis virus (SINV) infection. Quantitative proteomic analysis of host proteins associated with SINV capsid identified FXR2, an RNA-binding protein linked to stress granules and protein homeostasis. Co-immunoprecipitation and immunofluorescence confirmed that FXR2 associates and colocalizes with viral capsid in infected cells. Loss of FXR2 increased capsid accumulation, reduced LC3 lipidation and autophagosome formation, and impaired p62 degradation following infection. Reconstitution of FXR2-deficient cells restored autophagy and promoted capsid clearance. Although FXR2 deficiency did not significantly increase viral replication, it enhanced virus-induced cell death, suggesting that FXR2 protects infected cells by limiting viral protein toxicity rather than by directly restricting virus production. Consistent with this model, both Fxr2-null and heterozygous mice exhibited increased mortality following neurotropic SINV challenge, and Fxr2-null mice developed greater neuronal degeneration, inflammation, and cell death despite viral titers comparable to those in wild-type animals. Together, these findings identify FXR2 as a previously unrecognized component of the antiviral autophagy pathway that promotes viral capsid clearance and protects neural tissue from infection-associated damage.

microbiology↗

bioRxiv2026

Sequential infection reprograms the immune landscape to shape future responses

Mouse models have been instrumental in defining immune mechanisms but often fail to capture the complexity of human immunity, limiting clinical translation. A major limitation is the immunological immaturity of specific pathogen-free (SPF) mice relative to pathogen-experienced adult humans. Here, we use a sequential infection (SI) model that recapitulates cumulative pathogen exposure and define its impact on immune composition and function. Beyond the previously reported expansion of memory T cells, SI induced durable, system-wide remodeling across lymphoid and non-lymphoid tissues, reshaping innate and adaptive immune populations, tissue-resident immunity, and hematopoietic output. Single-cell transcriptomic analyses revealed inflammatory imprinting of naive CD4 and CD8 T cells, whereas memory T cells acquired enhanced effector programs coupled with reduced biosynthetic activity, transcriptional states that more closely resemble those of pathogen-experienced adult humans. Functionally, SI mice recapitulated the human response to anti-CD28 super-agonist and exhibited altered magnitude and differentiation of acute and chronic antiviral T cell responses, demonstrating that cumulative pathogen exposure reshapes both existing immunity and the generation of future immune responses. Thus, cumulative pathogen exposure coordinately remodels hematopoiesis and naive and memory lymphocyte states, establishing a durable inflammation-experienced immune landscape that reshapes both immune memory and future immune responses, with broad implications for the translational fidelity of preclinical mouse models.

immunology↗

bioRxiv2023

Norovirus MLKL-like pore forming protein initiates programed cell death for viral egress

Non-enveloped viruses require cell lysis to release new virions from infected cells, suggesting that these viruses require mechanisms to induce cell death. Noroviruses are one such group of viruses, but a mechanism of norovirus-infection triggered cell death and lysis are unknown. Here we have identified a molecular mechanism of norovirus-induced cell death. We found that the norovirus-encoded NTPase contains a N-terminal four helix bundle domain homologous to the pore forming domain of the pseudokinase Mixed Lineage Kinase Domain-Like (MLKL). Norovirus NTPase acquired a mitochondrial localization signal, thereby inducing cell death by targeting mitochondria. NTPase full length (NTPase-FL) and N-terminal fragment (NTPase-NT) bound mitochondrial membrane lipid cardiolipin, permeabilized mitochondrial membrane and induced mitochondrial dysfunction. Both the N-terminal region and the mitochondrial localization motif of NTPase were essential for cell death, virus egress from cells and virus replication in mice. These findings suggest that noroviruses stole a MLKL-like pore forming domain and co-opted it to facilitate viral egress by inducing mitochondrial dysfunction.

microbiology↗

bioRxiv2022

Coinfection with Intestinal Parasite Expands Resident Macrophages and Impairs Control of Chronic Herpesvirus Infection

In addition to a range of homeostatic functions, resident macrophages are essential for immune surveillance in tissues. Therefore, anything that alters the phenotype or function of these cells potentially impacts their response to infectious challenges. Parasite infections cause proliferation of large peritoneal macrophages (LPMs), which are the resident macrophages of the peritoneal cavity. However, the functional consequences of LPM expansion on the control of secondary infectious challenge is unknown. Using a coinfection model with the intestinal parasite Heligmosomoides polygyrus (HP) and the virus, murine gammaherpesvirus-68 (MHV68), we investigated the impact of LPM expansion on viral infection. We determined that LPM expansion induced by HP required retinoic acid signaling. When we challenged HP-infected mice with MHV68, we observed increased herpesvirus infection and latency. Coinfection of mice with macrophage-specific deletion of GATA6, the retinoic acid-responsive transcription factor that drives LPM transcriptional programming, eradicated the increase in viral infection. In addition to increased MHV68 infection, parasite coinfected mice displayed increased herpesvirus reactivation from latency, indicating impaired control of chronic herpesvirus infection. Elimination of dietary vitamin A, which depletes retinoic acid and LPMs, abolished the increased MHV68 reactivation in parasite coinfected mice. These results indicate that parasite- and retinoic acid-mediated resident macrophage expansion drives increased herpesvirus infection, latency, and reactivation.

immunology↗

bioRxiv2022

CDKL5 regulates p62-mediated selective autophagy and host antiviral defense

Virophagy, the selective autophagosomal engulfment and degradation of viral components, is crucial for antiviral immunity. However, the mechanisms leading to viral antigen recognition and autophagy induction remain poorly understood. Here, we identify a novel kinase, Cyclin-dependent kinase-like 5 (CDKL5), as an essential regulator of virophagy. Deletion of CDKL5 or abrogation of its kinase activity reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid proteins and cellular cytotoxicity. Mechanistically, through direct phosphorylation of the selective autophagy receptor p62, CDKL5 promoted formation of p62 inclusion bodies that bound capsid. Loss of CDKL5 disrupted the capsid-p62 interaction, and a p62 phosphomimetic mutant rescued the interaction. CDKL5 knockout mice demonstrated increased neuronal cell death after SINV infection and enhanced lethality after infection with several human viruses. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear toxic viral capsid aggregates during infection.

microbiology↗

bioRxiv2021

WY14643 Increases Herpesvirus Replication Independent of PPARα Expression and Inhibits IFNβ Production

Peroxisome proliferator activated receptor (PPAR) agonists are commonly used to treat metabolic disorders in humans because they regulate fatty acid oxidation and cholesterol metabolism. In addition to their roles in controlling metabolism, PPAR agonists also regulate inflammation and are immunosuppressive in models of autoimmunity. We aimed to test whether activation of PPAR with clinically relevant ligands could impact herpesvirus infection using the model strain murine gammaherpesvirus-68. We found that PPAR agonists WY14643 and fenofibrate increased herpesvirus replication in vitro. In vivo, WY14643 increased viral replication and caused lethality in mice. Unexpectedly, these effects proved independent of PPAR. Investigating the mechanism of action for WY14643, we found that it suppresses production of type I interferon by inhibiting stimulator of interferon (STING), which lies downstream of the cytoplasmic DNA sensor cGAS. Thus, WY14643 regulates interferon downstream of cytoplasmic DNA recognition and increases herpesvirus replication in a PPAR-independent manner. Taken together, our data indicate that caution should be employed when using PPAR agonists in immuno-metabolic studies, as they can have off-target effects on viral replication. ImportancePPAR agonists are used clinically to treat both metabolic and inflammatory disorders. Because viruses are known to rewire host metabolism to their own benefit, the intersection of immunity, metabolism, and virology is an important research area. Our article is an important contribution to this field because for two reasons. First, it shows a role for PPAR agonists in altering virus detection by cells. Second, it shows that PPAR agonists can affect virus replication in a manner unrelated to their expected genetic function. This knowledge is valuable for anyone seeking to use PPAR agonists as a research tool.

immunology↗

bioRxiv2020

Th2 Cytokine Modulates Herpesvirus Reactivation in a Cell Type Specific Manner

Gammaherpesviruses, such as Epstein-Barr virus (EBV), Kaposis sarcoma associated virus (KSHV), and murine {gamma}-herpesvirus 68 (MHV68), establish latent infection in B cells, macrophages, and non-lymphoid cells, and can induce both lymphoid and non-lymphoid cancers. Research on these viruses has relied heavily on immortalized B cell and endothelial cell lines. Therefore, we know very little about the cell type specific regulation of virus infection. We have previously shown that treatment of MHV68-infected macrophages with the cytokine interleukin-4 (IL-4) or challenge of MHV68-infected mice with an IL-4-inducing parasite leads to virus reactivation. However, we do not know if all latent reservoirs of the virus, including B cells, reactivate the virus in response to IL-4. Here we used an in vivo approach to address the question of whether all latently infected cell types reactivate MHV68 in response to a particular stimulus. We found that IL-4 receptor expression on macrophages was required for IL-4 to induce virus reactivation, but that it was dispensable on B cells. We further demonstrated that the transcription factor, STAT6, which is downstream of the IL-4 receptor and binds a viral promoter in macrophages, did not bind to the viral promoter in B cells. These data suggest that stimuli that promote herpesvirus reactivation may only affect latent virus in particular cell types, but not in others. ImportanceHerpesviruses establish life-long quiescent infections in specific cells in the body, and only reactivate to produce infectious virus when precise signals induce them to do so. The signals that induce herpesvirus reactivation are often studied only in one particular cell type infected with the virus. However, herpesviruses establish latency in multiple cell types in their hosts. Using murine gammaherpesvirus-68 (MHV68) and conditional knockout mice, we examined the cell type specificity of a particular reactivation signal, interleukin-4 (IL-4). We found that IL-4 only induced herpesvirus reactivation from macrophages, but not from B cells. This work indicates that regulation of virus latency and reactivation is cell type specific. This has important implications for therapies aimed at either promoting or inhibiting reactivation for the control or elimination of chronic viral infections.

microbiology↗

bioRxiv2019

Metabolic Control of Viral Infection through PPAR-α Regulation of STING Signaling

Peroxisomal proliferator activated receptors (PPARs) are sensors of dietary lipids and pharmacological targets in the treatment of metabolic disorders. PPAR ligands are also immunosuppressive. However, their function during infection is debated and the mechanisms that underlie their immunoregulatory properties are unclear. We investigated the consequences of PPAR activation during herpesvirus infection. We found that activation of PPAR- increased herpesvirus replication, suppressed type I interferon production and induced reactive oxygen species (ROS). We discovered that ROS induced by PPAR- stimulation suppressed the cytoplasmic DNA sensing pathway after direct activation of stimulator of interferon (STING), the ER adapter downstream of cytoplasmic DNA recognition. Although high ROS induces inflammasome activation and cytokine production, we found that ROS inhibited interferon production after cytoplasmic DNA recognition. Treatment of mice with a clinically relevant agonist of PPAR- increased herpesvirus replication and pathogenesis, comparable to levels observed previously in type I interferon receptor knockout mice. These findings reveal that activation of PPAR- regulates immunity to cytoplasmic DNA and DNA virus infection through inhibition of interferon. Moreover, these results demonstrate that STING signaling and interferon production is regulated by ROS.

immunology↗