Biology subjects

Klatt, N. R.

Publications and source records attributed to Klatt, N. R..

11 recordsLinked to original sources

bioRxiv2026

Spatial Transcriptomics Reveals Compartment-Specific Immune Activation Signatures in Ileal and Lymph Node Tissue in Treated HIV Infection

People with HIV (PWH) on long-term antiretroviral therapy (ART) continue to experience elevated rates of morbidities and mortality driven by persistent immune activation despite viral suppression. Known contributors include low-level HIV provirus activity, microbial translocation in part from epithelial barrier dysfunction, microbiome dysfunction, and co-infections. However, how these interact and where they predominate across tissue compartments remains incompletely defined. Here, we applied spatial transcriptomics to characterize compartment-specific transcriptional programs in ileum (epithelium, Peyer's patches, lamina propria) and inguinal lymph nodes (B Cell follicles and T cell zone) from ten PWH on long-term ART, stratified by CD4/CD8 ratio into low-ratio and high-ratio groups, with low-ratio as a proxy for immune activation and increased risk for non-AIDS related serious event. Comparison of global expression found significant differences between groups in four of five compartments. Differential expression analysis identified 483 differentially expressed genes across four of five compartments, with the greatest burden in the T-cell zone and none in the lamina propria. Gene set enrichment analysis identified 116 enriched pathways predominantly in the low-ratio group, spanning immune activation, infection-associated, and metabolic programs, with Peyer's patches showing the broadest transcriptional divergence of any compartment. Cross-compartment signals included higher expression of ORMDL3 and ARL17B in the low-ratio group implicating mitochondrial stress and inflammasome activation, lower expression of CCL3L3 and FCMR in the low-ratio group suggesting impaired immune execution, and divergent ribosomal protein programs between B-cell follicles and the T-cell zone. Cell deconvolution identified compartment-specific differences in estimated immune cell proportions, and T-cell zone gene expression showed significant associations with HIV reservoir measures and plasma markers of microbial translocation and immune activation. Together these findings support spatially heterogeneous immune activation as a feature of persistent immune dysregulation in treated HIV infection and provide compartment-resolved, hypothesis-generating evidence for the tissue-specific mechanisms driving inflammation in this population.

bioinformatics↗

bioRxiv2026

Plasma metabolomics reveals lipid-predominant metabolic disruptions in virologically suppressed people with HIV

People with HIV (PWH) on antiretroviral therapy (ART) experience excess morbidity and mortality from comorbidities including cardiovascular and metabolic disease, yet the biological mechanisms underlying these outcomes in virally suppressed PWH (VS-PWH) remain incompletely understood. We applied high-dimensional targeted plasma metabolomics to quantify 254 small molecules and 750 lipids across 49 classes in viremic PWH (Vi-PWH), VS-PWH, and people without HIV (PWoH), analyzed alongside multiple T cell metrics and plasma cytokine concentrations. Globally, the plasma metabolome of VS-PWH was indistinguishable from PWoH, while Vi-PWH exhibited substantial metabolic disruption characterized by depletion of phosphatidylcholines, sphingomyelins, and hexosylceramides alongside triglyceride accumulation, dysregulation of the tryptophan-kynurenine and arginine-citrulline axes, and elevations in diacetylated polyamines and N4-acetylcytidine. Ordinal trend analysis identified subtle but consistent residual alterations in VS-PWH, particularly within phosphatidylcholine and sphingomyelin classes, that correlated with elevated TNF and reduced CD4+ T cell counts and CD4/CD8 ratio. Together, these findings indicate that residual TNF-associated inflammation and incomplete T cell recovery continue to shape the plasma metabolome in treated HIV, identifying candidate biomarkers for further mechanistic and clinical investigation.

microbiology↗

bioRxiv2026

Multi-omics links microbial dysbiosis, systemic inflammation and metabolomic disruptions to SNAE risk in treated HIV

Serious non-AIDS events (SNAEs), including non-AIDS malignancies, cardiovascular disease, and hepatic complications, remain major causes of mortality in treated HIV infection. These outcomes are driven by persistent immune activation, systemic inflammation, and metabolic dysfunction despite effective viral suppression with antiretroviral therapy (ART). To investigate mechanisms underlying SNAE pathogenesis, we performed a cross-site multi-omic analysis integrating plasma proteins, plasma metabolites, and mucosal microbiomes (ileum and rectum) in 82 ART-treated people with HIV (PWH) and 10 people without HIV (PWoH) from the United States and Mexico. Geography was the dominant source of variation, particularly across lipid classes. However, individuals at high risk for SNAEs, defined by low CD4 T cell counts and low CD4/CD8 ratios, shared a consistent signature of systemic inflammation, mitochondrial dysfunction, and microbial dysbiosis including elevated plasma IL-6, {omega}-oxidation products (adipic and suberic acids), and depletion of short-chain fatty acid-producing commensals in the gut mucosa, including Akkermansia muciniphila, Bacteroides uniformis, and Ruminococcus. Notably, A. muciniphila abundance correlated with lower IL-6 levels, fewer HIV RNA-producing cells in lymph nodes, and higher CD4/CD8 ratios. Together, these findings identify a shared inflammatory and metabolic phenotype in PWH and implicate A. muciniphila as a potential microbiome-based target to mitigate immune activation and SNAE risk in treated HIV.

immunology↗

bioRxiv2026

Ongoing lymphoid HIV production drives pyroptosis and GLP-1 counter-regulation in ART-suppressed infection

Despite effective antiretroviral therapy (ART), many people with HIV (PWH) exhibit persistent immune activation (IA) and suffer metabolic comorbidities. We investigated whether residual HIV production in lymphoid tissues drives IA. Among 20 ART-suppressed PWH, HIV RNA+ cells were detected in lymph nodes and correlated directly with markers of pyroptosis, assessed via cleaved gasdermin D positivity, but not with most plasma cytokines or IA markers. Notably, glucagon-like peptide 1 (GLP-1), an enteroendocrine hormone with anti-inflammatory roles, was upregulated in the ileum of PWH and correlated directly with systemic cytokines but inversely with lymph node pyroptosis. These findings suggest that chronic occult inflammation in people with successfully suppressed HIV infection is mediated by persistent virus production in lymph nodes leading to pyroptosis, which may trigger compensatory anti-inflammatory enteroendocrine activation that may dampen pyroptosis. Targeting pyroptosis or enhancing GLP-1 signaling represent potential therapeutic strategies for modulating IA and managing metabolic comorbidities in PWH. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/698696v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@af8909org.highwire.dtl.DTLVardef@4dbc95org.highwire.dtl.DTLVardef@197ff48org.highwire.dtl.DTLVardef@1f9051a_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Pre-treatment Microbiome Diversity and Function is associated with Expansion of Cytotoxic and Regulatory Immune Populations after N-803 treatment in People with HIV

BackgroundN-803, an IL-15 superagonist, is currently being studied in clinical trials as a treatment to reverse HIV latency. However, its effects on the gut microbiome are not well understood. MethodsIn this longitudinal metagenomic study, we analyzed fecal microbiomes from ART-suppressed people with HIV at four different timepoints before, during, and after N-803 treatment. ResultsOverall taxonomic and functional diversity did not change significantly, yet beneficial microbial taxa and pathways were enriched after N-803. Specifically, the relative abundance of Faecalibacterium prausnitzii increased significantly after N-803, whereas histidine degradation pathways, often associated with pro-inflammatory mucosal state, decreased. A higher baseline microbial diversity correlated with stronger CD8+ and natural killer (NK) cells activation and reduced frequency of rectal HIV RNA+ cells. MaAsLin2 analyses further associated short-chain fatty acid (SCFA)-producing taxa and pathways with increased immune activation markers. ConclusionsThese results indicate that gut microbiome diversity prior to immunotherapy influences host response and suggest that microbiome-based strategies could improve efforts to cure HIV.

microbiology↗

bioRxiv2025

The cervicovaginal microbiome of pregnant people living with HIV on antiretroviral therapy in the Democratic Republic of Congo: A Pilot Study and Global Meta-analysis.

Recent studies are revealing that a suboptimal cervicovaginal microbiome (CVMB), including enrichment of anaerobic bacteria associated with multiple female genital disorders, and adverse pregnancy and birth outcomes in pregnant people. Problematically, however, the majority of the available data to date are biased towards highly developed, Global North countries, leaving underrepresented populations like the Democratic Republic of Congo (DRC) poorly characterised. Here, we investigate the CVMB from a cohort of 82 pregnant people living with HIV (PLWH) on antiretroviral therapy (ART) from the DRC. Specifically, we explore the associations between the CVMB via 16S rRNA gene sequencing and maternal peripheral immune factors. Additionally, we compare the CVMB of PLWH-ART from DRC to publicly available CVMB data (5 studies, 1861 samples) in a meta-analysis to elucidate the impact of HIV on the CVMB. Combined, these analyses revealed differences in community structure and predicted function of the microbiota between PLWH-ART and pregnant people without HIV (PWoH). Taxonomically, the CVMB of DRC PLWH-ART were enriched for Lactobacillus iners-dominated CVMBs (53%) or a diverse, polymicrobial CVMB, i.e., bacterial vaginosis (BV) (43%). Functional predictions made from these taxa suggested that protein-coupled receptors, amino sugar and nucleotide sugar metabolism, fatty acid metabolism, and polycyclic aromatic hydrocarbon degradation pathways were differentially abundant between communities. Correlation with host plasma immune factors revealed putative links between some CVMB metrics (e.g., alpha diversity and species abundance) that have been linked to adverse pregnancy and birth outcomes. ImportanceHIV remains prevalent in sub-Saharan Africa, where it has been linked to adverse birth outcomes. . Suboptimal CVMBs have shown similar links. This pilot study fills critical gaps in understanding how HIV interacts with the pregnant CVMB in populations underrepresented in microbiome research, like the Democratic Republic of Congo. We identified maternal systemic immune factors associated with suboptimal CVMBs that have been linked to poor birth outcomes. In a global meta-analysis, we found significant taxonomic and functional difference in the CVMBs between pregnant people living with and without HIV, revealing potential biomarkers that for increased risks for adverse birth outcomes. These findings provide crucial insights into CVMB features that may influence pregnancy health in pregnant people living with HIV, guiding future research and tailored interventions to support safer pregnancies in the DRC and similar populations.

microbiology↗

bioRxiv2025

Gut barrier integrity biomarkers are associated with increased inflammation and predict disease status in hospitalized COVID-19 patients

The COVID-19 global pandemic persists as an endemic disease with frequent case spikes and a significant continued burden on public health. Although most COVID-19 cases are asymptomatic or mild, severe infections requiring hospitalization have resulted in likely more than 14 million cumulative deaths to date. One hallmark of severe COVID-19 is a dysregulated immune response that leads to systemic inflammation and contributes to disease severity and mortality but is not explained by viral replication alone. Severe COVID-19 has been shown to disrupt the gut microbiome and increase intestinal permeability which may contribute to immune dysregulation and systemic inflammation. In this study, we investigated the differences in plasma biomarkers for microbial translocation and gut barrier damage as well as circulating cytokines between healthy volunteers and patients hospitalized with COVID-19. We then performed a correlation analysis to understand how the relationships between these plasma biomarkers differed and used a random forest model to assess their accuracy in distinguishing between these two groups. Our results demonstrated that hospitalized COVID-19 patients have elevated concentrations of pro-inflammatory cytokines and markers of microbial translocation, and that the relationships between these biomarkers were significantly altered compared to healthy volunteers, especially those related to the mucosal associated homeostatic cytokines IL-17A and IL-23. Furthermore, IL-6 and LBP were the top biomarkers for prediction accuracy in our random forest model, highlighting the importance of managing microbial translocation in COVID-19 and its potential utility as a biomarker for disease severity. IMPORTANCECOVID-19 continues to be a burden on public health. Understanding how plasma biomarkers differ between healthy and acutely infected individuals can help in understanding pathogenesis and predict disease severity. It has been demonstrated that COVID-19 disrupts the gut microbiome and intestinal permeability, which contributes to systemic inflammation. Our study highlights the link between gut barrier integrity and inflammation in hospitalized SARS-CoV-2 cases, demonstrating the usefulness of gut barrier integrity biomarkers in predicting disease severity, and offers insights for therapeutic interventions in acute COVID-19 infection.

immunology↗

bioRxiv2023

SARS-CoV-2 infection is associated with intestinal permeability, systemic inflammation, and microbial dysbiosis in hospitalized COVID-19 patients

Coronavirus disease 2019 (COVID-19) and associated severity has been linked to uncontrolled inflammation and may be associated with changes in the microbiome of mucosal sites including the gastrointestinal tract and oral cavity. These sites play an important role in host-microbe homeostasis and disruption of epithelial barrier integrity during COVID-19 may potentially lead to exacerbated inflammation and immune dysfunction. Outcomes in COVID-19 are highly disparate, ranging from asymptomatic to fatal, and the impact of microbial dysbiosis on disease severity is unclear. Here, we obtained plasma, rectal swabs, oropharyngeal swabs, and nasal swabs from 86 patients hospitalized with COVID-19 and 12 healthy volunteers. We performed 16S rRNA sequencing to characterize the microbial communities in the mucosal swabs and measured circulating cytokines, markers of gut barrier integrity, and fatty acids in the plasma samples. We compared these plasma concentrations and microbiomes between healthy volunteers and the COVID-19 patients who had survived or unfortunately died by the end of study enrollment, and between severe disease and healthy controls, as well as performed a correlation analysis between plasma variables and bacterial abundances. The rectal swabs of COVID-19 patients had reduced abundances of several commensal bacteria including Faecalibacterium prausnitsii, and an increased abundance of the opportunistic pathogens Eggerthella lenta and Hungatella hathewayi. Furthermore, the oral pathogen Scardovia wiggsiae was more abundant in the oropharyngeal swabs of COVID-19 patients who died. The abundance of both H. hathewayi and S. wiggsiae correlated with circulating inflammatory markers including IL-6, highlighting the possible role of the microbiome in COVID-19 severity, and providing potential therapeutic targets for managing COVID-19.

microbiology↗

bioRxiv2023

Elevated peripheral and nervous system inflammation is associated with decreased short-chain fatty acid levels in Zika-virus infected macaques

Zika virus (ZIKV) infection of central nervous system (CNS) tissue is associated with CNS inflammation, which contributes to ZIKV pathology. Similarly, ZIKV infection has been associated with increased vaginal and rectal mucosal inflammation. As mucosal dysfunction may contribute to elevated systemic inflammation, ZIKV-induced mucosal alterations could potentiate CNS disruptions, leading to ZIKV pathogenesis. However, the potential link between mucosal dysfunction, CNS inflammation and the underlying mechanisms causing these disruptions in ZIKV infection has not been well described. Here, we assessed plasma and CSF indicators of inflammation, including neopterin, tryptophan, kynurenine and serotonin by liquid chromatography tandem mass spectrometry. We observed significant increases in neopterin formation, tryptophan catabolism and serotonin levels in the plasma and CSF of ZIKV-infected pigtail macaques (PTM), rhesus macaques (RM) and in the plasma of ZIKV-infected humans. We next examined whether ZIKV infection resulted in microbial translocation across mucosal surfaces by evaluating plasma and cerebrospinal fluid (CSF) levels of soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP) by enzyme-linked immunosorbent assay (ELISA). Increased sCD14 was observed in the CSF of PTM and rhesus macaque (RM), while increased LBP was observed in pigtail macaque (PTM) plasma. Finally, to examine whether ZIKV-induced microbial dysbiosis could underlie increased microbial translocation and inflammation, we characterized intestinal microbial communities by 16s rRNA gene sequencing and microbial functional changes by quantifying short-chain fatty acid (SCFA) concentrations by gas chromatography mass spectrometry. We observed that although ZIKV infection of PTM did not result in significant taxonomic shifts in microbial communities, there were significant reductions in SCFA levels. Loss of microbial function in ZIKV infection could cause decreased intestinal integrity, thereby contributing to elevated microbial translocation and systemic and CNS inflammation, providing a possible mechanism underlying ZIKV pathogenesis. Further, this may represent a mechanism underlying inflammation and pathogenesis in other diseases. Author SummaryZika virus (ZIKV) can be transmitted to humans via the bite of an infected mosquito or between humans during sexual intercourse, typically resulting in mild symptoms, which has been linked to elevated inflammation in the CNS and the development of more serious conditions, including severe neurological syndromes. Previous studies have observed that ZIKV infection is associated with increased mucosal dysfunction, including elevated inflammation in rectal and vaginal mucosal tissue. However, the mechanism of ZIKV-induced mucosal dysfunction may contribute to systemic and CNS inflammation has not been previously investigated. Here, we used the non-human primate (NHP) model and clinical specimens from ZIKV-infected humans to examine markers of systemic and CNS inflammation and microbial translocation. We observed elevated markers indicative of microbial translocation and inflammation in the CNS of ZIKV-infected macaques and humans. A potential association with mucosal dysfunction in ZIKV infection is shifts in microbial dysbiosis. We also observed that there were no significant overall taxonomic shifts in microbial communities, but a reduction of bacterial-derived short-chain fatty acid (SCFA) levels. Finally, we observed that the decrease in SCFA levels significantly negatively correlated with the elevated peripheral and CNS inflammatory markers, suggesting a link between ZIKV-driven disease pathology and microbial function. Taken together, our study provides new insight into a previously unconsidered mechanism underlying ZIKV pathogenesis.

microbiology↗

bioRxiv2022

High-risk microbial signatures are associated with severe parasitemia in controlled Plasmodium infections of both humans and rhesus macaques

While functions of the gastrointestinal (GI) microbiome include maintenance of immune homeostasis and protection against infectious disease, its role in determining disease severity during Plasmodium infection has been limited to mouse models and observational human cohorts. Here, we performed controlled Plasmodium infection in both humans and rhesus macaques (RMs) to experimentally determine the impact of GI microbiome composition on disease progression. Through analysis of serially collected microbiome samples, we identified a high-risk microbial signature that strongly associated with increased risk of developing severe parasitemia in human participants. Importantly, we identified a parallel phenomenon in RMs. The combined weight of this evidence demonstrates that pre-infection GI microbiome composition is highly indicative of P. falciparum disease risk. Moreover, our observation that P. fragile-microbiome dynamics in RMs closely mirrors P. falciparum-microbiome interactions in humans strongly supports the use of this model in pre-clinical investigations of novel microbiome-targeting approaches to reduce malaria burden.

microbiology↗

bioRxiv2020

Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity

The human microbiota has a close relationship with human disease and it remodels components of the glycocalyx including heparan sulfate (HS). Studies of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike protein receptor binding domain suggest that infection requires binding to HS and angiotensin converting enzyme 2 (ACE2) in a codependent manner. Here, we show that commensal host bacterial communities can modify HS and thereby modulate SARS-CoV-2 spike protein binding and that these communities change with host age and sex. Common human-associated commensal bacteria whose genomes encode HS-modifying enzymes were identified. The prevalence of these bacteria and the expression of key microbial glycosidases in bronchoalveolar lavage fluid (BALF) was lower in adult COVID-19 patients than in healthy controls. The presence of HS-modifying bacteria decreased with age in two large survey datasets, FINRISK 2002 and American Gut, revealing one possible mechanism for the observed increase in COVID-19 susceptibility with age. In vitro, bacterial glycosidases from unpurified culture media supernatants fully blocked SARS-CoV-2 spike binding to human H1299 protein lung adenocarcinoma cells. HS-modifying bacteria in human microbial communities may regulate viral adhesion, and loss of these commensals could predispose individuals to infection. Understanding the impact of shifts in microbial community composition and bacterial lyases on SARS-CoV-2 infection may lead to new therapeutics and diagnosis of susceptibility. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/238444v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@14ff1ecorg.highwire.dtl.DTLVardef@193d84corg.highwire.dtl.DTLVardef@15d6f9eorg.highwire.dtl.DTLVardef@14b16c6_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract. Diagram of hypothesis for bacterial mediation of SARS-CoV-2 infection through heparan sulfate (HS).It is well known that host microbes groom the mucosa where they reside. Recent investigations have shown that HS, a major component of mucosal layers, is necessary for SARS-CoV-2 infection. In this study we examine the impact of microbial modification of HS on viral attachment. C_FIG

microbiology↗