Krystal J. Vail

RNA-binding proteins are key players in determining the fate of mRNA. One such RNA binding protein, Fragile X messenger ribonucleoprotein (FMRP), has an established role in RNA transcription, metabolism, translation, and degradation in the brain and reproductive system. Although FMRP is expressed in immune cells, little is known about how FMRP influences immune cell mRNA transcript outcomes. Here, we show that macrophage infection with the intracellular pathogen Listeria monocytogenes induces FMRP translocation from the cytoplasm to the nucleus. We show that infected macrophages lacking FMRP have impaired Il6 induction in response to L. monocytogenes infection. Finally, we show that macrophages lacking FMRP have increased susceptibility to inflammatory cell death. Together, these data implicate FMRP in modulating proinflammatory gene expression during bacterial infection.

: The anatomical and immunological similarities between humans and nonhuman primates (NHPs) make NHPs a viable model for examining Plasmodium spp. infection outcomes. Plasmodium fragile was previously used to model human severe malaria in NHPs using rhesus macaques (RMs), but a thorough investigation of the clinical and pathological effects of RM P. fragile infection has not yet been conducted. In this study, we observed that experimental infection of a male RM with P. fragile- infected erythrocytes resulted in clinical signs of malaria, including anemia; changes in red and white blood cell distribution; changes in red blood cell morphology; and gross and histopathological alterations to vital organs, such as the liver, lungs, heart, and brain. Plasmodium fragile- infected red blood cells were also observed in the vasculature of major organs, including the spleen, liver, lung, and brain. These results suggest that experimental P. fragile infection of RMs is a translatable model of human malaria.

Aliarcobacter butzleri is a Campylobacter -like bacteria associated with watery diarrhea in humans and is infrequently reported in nonhuman primate (NHP) populations. While clinical and microscopic features in humans are indistinguishable from Campylobacter spp. infection, descriptions of A. butzleri -associated colitis in NHP are lacking. Here, we describe the clinical and pathological features of diarrhea and colitis associated with A. butzleri in rhesus macaques using a retrospective approach. Over a 3-year period, A. butzleri was isolated from 10 macaques with diarrhea. Five of the 10 were submitted for necropsy and had features of chronic enterocolitis, consistent with existing literature. However, 40% (2/5) of the cases were characterized by ulcerative colitis, which has not previously been described as a feature of A. butzleri colitis. A. butzleri should be considered a differential diagnosis in cases of diarrhea and enterocolitis in captive rhesus macaques.

Persistent neurological symptoms are frequently reported following SARS-CoV-2 infection, yet the underlying neuropathology of post-acute sequelae of COVID-19 (PASC) remains unclear. Here, we characterize long-term brain changes in African green monkeys (AGMs) at 18 weeks post-infection (wpi). While neuronal apoptosis and microhemorrhages largely resolved by 18 wpi, chronic neuroinflammation persisted, with pronounced microglial and astrocyte activation and increased microglial nodule formation in the brainstem and cerebellum. Hypoxia-inducible factor-1 α (HIF-1 α) remained elevated in brain endothelial cells despite normoxia, implicating non-hypoxic stabilizing mechanisms. Cerebrospinal fluid metabolomics revealed altered branched-chain amino acids, cortisol, adenosine, and tricarboxylic acid cycle metabolites, consistent with sustained immunometabolic reprogramming. Behaviorally, infected AGMs showed reduced cognitive engagement and gustatory deficits. These data suggest that SARS-CoV-2 induces long-lasting neuroimmune and metabolic disturbances that may underlie persistent symptoms and contribute to premature neurodegeneration.

While viral pathogens are often subdivided into neurotropic and non-neurotropic categories, systemic inflammation caused by non-neurotropic viruses still possesses the ability to alter the central nervous system (CNS). Studies of CNS disease induced by viral infection, whether neurotropic or not, are presented with a unique set of challenges. First, because brain biopsies are rarely necessary to diagnose viral-associated neurological disorders, antemortem tissue samples are not readily available for study and human pathological studies must rely on end-stage, postmortem evaluations. Second, in vitro models fail to fully capture the nuances of an intact immune system, necessitating the use of animal models to fully characterize pathogenesis and identify potential therapeutic approaches. Non-human primates (NHP) represent a particularly attractive animal model in that they overcome many of the limits posed by more distant species and most closely mirror human disease pathogenesis and susceptibility. Here, we review NHP infection models of viruses known to infect and/or replicate within cells of the CNS, including West Nile virus, the equine encephalitis viruses, Zika virus, and herpesviruses, as well as those known to alter the immune status of the brain in the absence of significant CNS penetrance, including human immunodeficiency virus (HIV) in the current era of combination antiretroviral therapy (cART) and the coronavirus of severe acute respiratory syndrome (SARS)-CoV−2. This review focuses on viruses with an established role in causing CNS disease, including encephalitis, meningitis, and myelitis and NHP models of viral infection that are directly translatable to the human condition through relevant routes of infection, comparable disease pathogenesis, and responses to therapeutic intervention.

Cardiac exposure to ionizing radiation can damage both the microvasculature and coronary arteries, as well as increase the long-term risk of heart disease, myocardial fibrosis, and conduction abnormalities. Therapeutic agents capable of promoting recovery from radiation injury to the heart are limited. Growth hormone is linked to improved cardiac function following injury. Here, we leveraged a cynomolgus macaque model to determine the long-term outcomes of recombinant human growth hormone (rhGH) therapy on the heart following low-dose ionizing radiation. Macaques were exposed to 2 Gy radiation, treated with rhGH for one month, and assessed after 2 years. Overall, plasma lipid profile, cardiac function, and coronary artery disease were similar between rhGH and placebo treated animals. However, a subgroup of rhGH-treated animals exhibited more extensive atherosclerotic plaques in the coronary arteries. Together, these findings indicate that transient human growth hormone therapy subsequent to a single low dose of ionizing radiation involving the heart does not result in long-term changes to plasma cholesterol but may promote exacerbated coronary artery disease in a subset of individuals.

Rhodococcus equiis a major cause of foal pneumonia and an opportunistic pathogen in immunocompromised humans. While alveolar macrophages constitute the primary replicative niche forR.equi, little is known about how intracellularR. equiis sensed by macrophages. Here, we discovered that in addition to previously characterized pro-inflammatory cytokines (e.g.,Tnfa,Il6,Il1b), macrophages infected withR.equiinduce a robust type I IFN response, includingIfnband interferon-stimulated genes (ISGs), similar to the evolutionarily related pathogen,Mycobacterium tuberculosis. Follow up studies using a combination of mammalian and bacterial genetics demonstrated that induction of this type I IFN expression program is largely dependent on the cGAS/STING/TBK1 axis of the cytosolic DNA sensing pathway, suggesting thatR.equiperturbs the phagosomal membrane and causes DNA release into the cytosol following phagocytosis. Consistent with this, we found that a population of ~12% ofR.equiphagosomes recruits the galectin-3,-8 and -9 danger receptors. Interestingly, neither phagosomal damage nor induction of type I IFN require theR.equi’s virulence-associated plasmid. Importantly,R.equiinfection of both mice and foals stimulates ISG expression, in organs (mice) and circulating monocytes (foals). By demonstrating thatR.equiactivates cytosolic DNA sensing in macrophages and elicits type I IFN responses in animal models, our work provides novel insights into howR.equiengages the innate immune system and furthers our understanding how this zoonotic pathogen causes inflammation and disease.

Rhodococcus equi is a major cause of foal pneumonia and an opportunistic pathogen in immunocompromised humans. While alveolar macrophages constitute the primary replicative niche for R. equi , little is known about how intracellular R. equi is sensed by macrophages. Here, we discovered that that in addition to previously characterized pro-inflammatory cytokines (e.g., Tnfa, Il6, Il1b), macrophages infected with R. equi induce a robust type I IFN response, including Ifnb and interferon-stimulated genes (ISGs), similar to the evolutionarily related pathogen, Mycobacterium tuberculosis . Follow up studies using a combination of mammalian and bacterial genetics, demonstrated that induction of this type I IFN expression program is largely dependent on the cGAS/STING/TBK1 axis of the cytosolic DNA surveillance pathway, suggesting that R. equi perturbs the phagosomal membrane and causes DNA release into the cytosol following phagocytosis. Consistent with this we found that a population of ~12% of R. equi phagosomes recruited the galectin-3, −8 and −9 danger receptors. Interesting, neither phagosomal damage nor induction of type I IFN required the R. equi ’s virulence-associated plasmid. Importantly, R. equi infection of both mice and foals stimulated ISG expression, in organs (mice) and circulating monocytes (foals). By demonstrating that R. equi activates cytosolic DNA sensing in macrophages and elicits type I IFN responses in animal models, our work provides novel insights into how R. equi engages the innate immune system and furthers our understanding how this zoonotic pathogen causes inflammation and disease. IMPORTANCE: Rhodococcus equi is a facultative intracellular bacterial pathogen of horses and other domestic animals, as well as an opportunistic pathogen of immunocompromised and rarely immunocompetent humans. In human patients, Rhodococcus pneumonia bears some pathological similarities to pulmonary tuberculosis, and poses a risk for misdiagnosis. In horses, R. equi infection has a major detrimental impact on the equine breeding industry due to a lack of an efficacious vaccine and its ubiquitous distribution in soil. Given the prevalence of subclinical infection and high false positive rate in current screening methods, there exists a critical need to identify factors contributing to positive patient outcomes. Our research identifies innate immune sensing events and immune transcriptional signatures that may lead to biomarkers for clinical disease, more accurate screening methods, and insight into susceptibility to infection.

The Parkinson’s disease (PD)-associated gene leucine-rich repeat kinase 2 (LRRK2) has been studied extensively in the brain. However, several studies have established that mutations in LRRK2 confer susceptibility to mycobacterial infection, suggesting LRRK2 also controls immunity. We demonstrate that loss of LRRK2 in macrophages induces elevated basal levels of type I interferon (IFN) and interferon stimulated genes (ISGs) and causes blunted interferon responses to mycobacterial pathogens and cytosolic nucleic acid agonists. Altered innate immune gene expression in Lrrk2 knockout (KO) macrophages is driven by a combination of mitochondrial stresses, including oxidative stress from low levels of purine metabolites and DRP1-dependent mitochondrial fragmentation. Together, these defects promote mtDNA leakage into the cytosol and chronic cGAS engagement. While Lrrk2 KO mice can control Mycobacterium tuberculosis (Mtb) replication, they have exacerbated inflammation and lower ISG expression in the lungs. These results demonstrate previously unappreciated consequences of LRRK2-dependent mitochondrial defects in controlling innate immune outcomes.