Biology subjects

Bosinger, S. E.

Publications and source records attributed to Bosinger, S. E..

At least 19 recordsLinked to original sources

bioRxiv2026

Germinal centers can persist for up to one year with declining somatic hypermutation and ongoing plasma cell output

The total duration of primary germinal center (GC) responses, and how B cell evolution changes as these responses mature, remain poorly defined. Here, longitudinal sampling of rhesus macaques immunized with HIV Envelope protein revealed that a single slow-delivery prime sustained ongoing GCs for nearly a year without additional antigen. Somatic hypermutation (SHM) accumulated throughout these prolonged responses, but its rate declined substantially over time, independent of both priming strategy and boosting. Over the same period, subdominant non-base Env specificities became increasingly represented within the GC response. Delaying boosting until after primary GC contraction increased recruitment of recalled memory B cells into the GC response. Bone marrow plasma cells were generated throughout prolonged GC maturation, with the timing of their generation modulated by booster timing. Together, these findings reveal how GCs evolve across nearly a year and how this prolonged maturation shapes the memory and plasma cell compartments that underpin long-term humoral immunity.

immunology↗

bioRxiv2026

Inhibition of Stemness Pathways during Acute SIV Limits Infection of Central Memory CD4+ T Cells and Alters Viral Reservoir Activity in Macaques

The establishment of a reservoir of latently infected CD4+ T cells that persist on antiretroviral therapy (ART) through proliferation represents the main barrier to HIV cure. Here, we evaluated in macaques a therapeutic approach targeting Wnt and Notch pathways that regulate T cell proliferation and differentiation during acute SIV infection, when the viral reservoir is seeded. The combination of PRI-724 and LY3039478 led to reprogramming of central memory CD4+ T cells away from quiescence and stemness toward a metabolically active effector profile resulting in reduced infection of central memory CD4+ T cells. Following sustained ART, levels of SIV RNA in CD4+ T cells were higher in the PRI-724 + LY3039478-treated group compared to controls, although SIV DNA was similar. These findings suggest that stemness pathway inhibition promotes memory T cell differentiation leading to a more transcriptionally active reservoir and has potential to synergize with "shock-and-kill" approaches to reduce HIV persistence.

microbiology↗

bioRxiv2026

Co-delivered PD-L1 rescues the protective efficacy mediated by an AAV-expressed HIV-1 bNAb

Adeno-associated virus (AAV)-delivered anti-HIV-1 broadly neutralizing antibodies (bNAbs) could prevent and treat HIV-1 infection but are limited by host immune responses, specifically anti-drug antibodies (ADA). We tested whether PD-L1-mediated immune shielding could improve the consistency of AAV-delivered bNAb expression from muscle tissue in rhesus macaques. AAV9.PD-L1 co-delivery with AAV9.3BNC117 reduced the occurrence of ADA and T cell responses and improved the durability of 3BNC117 expression for one year post administration. Importantly, 5 of 6 macaques that received co-delivered AAV9.PD-L1 vectors were protected against ten repeated SHIVAD8-EO challenges. Histopathological and spatial transcriptomic profiling showed that AAV9.PD-L1 co-delivery prevented severe local inflammation, muscle injury, and tertiary lymphoid structure formation at the administration site. Thus, immune shielding could serve as a strategy to prolong transgene expression from muscle-directed AAV-delivered biologics.

immunology↗

bioRxiv2026

Overcoming host immune responses to an AAV-delivered HIV-1 bNAb in rhesus macaques mediated by co-delivery of PD-L1

Adeno-associated virus (AAV)-delivered anti-HIV-1 broadly neutralizing antibodies (bNAbs) have demonstrated promise for preventing and treating HIV-1 infection in preclinical models. However, host immune responses, specifically anti-drug antibodies (ADA), limit sustained bNAb expression. We have previously shown that PD-L1-mediated immune shielding improves the consistency of AAV-delivered bNAb 3BNC117 expression from muscle tissue in rhesus macaques. Here, we test the breadth of this approach with another bNAb, 10-1074. We show that AAV9.PD-L1 co-delivery with AAV9.10-1074 reduced the occurrence of ADA responses and improved the durability of bNAb expression for one year post administration. Notably 12 of 12 macaques that received AAV9.10-1074 vectors were protected against ten repeated SHIVAD8-EO challenges. Histopathological profiling showed that AAV9.PD-L1 co-delivery prevented severe local inflammation and tertiary lymphoid structure formation at the administration site. Thus, immune shielding could serve as a broad strategy to prolong transgene expression from muscle-directed AAV-delivered biologics.

immunology↗

bioRxiv2026

Mechanisms of disrupted neurodevelopment after Zika virus infection in infancy

Congenital and early-life Zika virus (ZIKV) infection can result in neurologic deficits. Precise mechanisms of injury, especially in the more subtle presentation of postnatal infection, are not fully elucidated. Here, we defined the effects of ZIKV on the developing brain using single cell transcriptomics, histopathology and design-based stereology, diffusion MRI, and neurobehavioral assessments in infant rhesus macaques. ZIKV upregulated interferon-stimulated genes in activated microglia and cell death pathways in neurons and downregulated metabolism and differentiation genes in mature oligodendrocytes. Abnormal micro-organization of the corpus collosum and limbic white matter tracts was seen on diffusion weighted imaging. A curated gene set associated with autism spectrum disorder risk was negatively enriched in inhibitory and excitatory neurons from ZIKV-infected infants, with increased emotional reactivity already evident two weeks following infection. From single cells to organism-level behaviors, these results define the pathways and processes disrupted by early-life ZIKV infection.

neuroscience↗

bioRxiv2025

Non-human primate LIBRA-Seq accelerates neutralizing antibody discovery in RM vaccinated against HIV-1

Broadly neutralizing antibodies (bNAbs) exhibit protective efficacy against HIV-1 infection making them an ideal archetype for HIV-1 vaccine design. Presently, no vaccine candidate has induced antibody responses capable of meaningful protection against the swathe of circulating, difficult to neutralize tier 2 HIV-1 viruses. However, the development of stabilized, native-like envelope (Env) trimers such as BG505.SOSIP.664.T332N (BG505 SOSIP) has marked a significant advancement in vaccine design, due to their ability to elicit NAbs that neutralize tier 2 viruses in rhesus macaques (RM). NAb development following envelope trimer immunization in RM remains poorly understood, with hypothesized contributions from genetic variation at the IG loci, naive B cell repertoire, and differential gene expression in B cell lineages. To address these knowledge gaps, we have developed a set of BG505 SOSIP probes capable of recovering paired clonotype identity, antigen specificity, and gene expression of B cells in a high throughput fashion. These probes were constructed by conjugating biotinylated BG505 SOSIP to streptavidin covalently linked to both sc-RNA-Seq compatible DNA oligonucleotides and flow cytometry compatible fluorophores. Using these reagents, we isolated and sequenced BG505 SOSIP specific memory B cells from the PBMCs of an RM that developed high titers of neutralizing antibodies. To benchmark the accuracy of our technology, we compared our recovered heavy and light chain sequences to those identified from the same animal using conventional methodology and recovered 100% of previously identified NAbs. We then applied this technology to recover BG505 SOSIP specific memory B cells from five additional vaccinated RMs, cloned 34 antibodies for functional characterization, and identified ten antibodies with autologous neutralizing activity. Author SummaryUnderstanding how effective antibodies arise after HIV vaccination is essential for developing a protective vaccine, yet studying these responses in non-human primates has been limited by low- throughput methods. In this study, we adapted a high-throughput single-cell sequencing approach to identify HIV envelope-specific antibodies from vaccinated rhesus macaques. This method allowed us to recover paired antibody sequences together with their antigen specificity from thousands of individual B cells. We successfully identified known neutralizing antibodies and discovered additional antibodies capable of neutralizing HIV across multiple animals. Our analysis revealed that vaccine-elicited antibody responses were dominated by a small number of expanded lineages, with shared genetic features among animals with stronger neutralization. These findings demonstrate that this approach can efficiently define the antibody repertoires generated by HIV vaccines and provide a powerful tool for evaluating and improving immunogens in preclinical vaccine studies.

immunology↗

bioRxiv2025

Identification of a multi-omics factor predictive of long COVID in the IMPACC study

Following SARS-CoV-2 infection, [~]10-35% of COVID-19 patients experience long COVID (LC), in which often debilitating symptoms persist for at least three months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities. We utilized machine learning methods on biologic analytes and patient reported outcome surveys provided over 12 months after hospital discharge from >500 hospitalized COVID-19 patients in the IMPACC cohort to identify a multi-omics "recovery factor". IMPACC participants who experienced LC had lower recovery factor scores compared to participants without LC. Biologic characterization revealed increased levels of plasma proteins associated with inflammation, elevated transcriptional signatures of heme metabolism, and decreased androgenic steroids in LC patients. The recovery factor was also associated with altered circulating immune cell frequencies. Notably, recovery factor scores were predictive of LC occurrence in patients as early as hospital admission, irrespective of acute disease severity. Thus, the recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.

systems biology↗

bioRxiv2025

A Broad Survey and Functional Analysis of Immunoglobulin Loci Variation in Rhesus Macaques

Rhesus macaques (RMs) are a vital model for studying human disease and invaluable to pre-clinical vaccine research, particularly for the study of broadly neutralizing antibody responses. Such studies require robust genetic resources for antibody-encoding genes within the immunoglobulin (IG) loci. The complexity of the IG loci has historically made them challenging to characterize accurately. To address this, we developed novel experimental and computational methodologies to generate the largest collection to date of integrated antibody repertoire and long-read genomic sequencing data in 106 Indian origin RMs. We created a comprehensive resource of IG heavy and light chain variable (V), diversity (D), and joining (J) alleles, as well as leader, intronic, and recombination signal sequences (RSSs), including the curation of 1474 novel alleles, unveiling tremendous diversity, and expanding existing IG allele sets by 60%. This publicly available, continually updated resource (https://vdjbase.org/reference_book/Rhesus_Macaque) provides the foundation for advancing RM immunogenomics, vaccine discovery, and translational research.

immunology↗

bioRxiv2024

Diverse priming outcomes under conditions of very rare precursor B cells

Rare B cells can have special pathogen-recognition features giving them the potential to make outsized contributions to protective immunity. However, rare naive B cells infrequently participate in immune responses. We investigated how germline-targeting vaccine antigen delivery and adjuvant selection affect priming of exceptionally rare BG18-like HIV broadly neutralizing antibody-precursor B cells (~1 in 50 million) in non-human primates. Only escalating dose (ED) priming immunization using the saponin adjuvant SMNP elicited detectable BG18-like cells in germinal centers (GCs). All groups had strong GC responses, but only ED+SMNP and bolus+SMNP induced BG18-like memory B cells in >50% of animals. One group had vaccine-specific GC responses equivalent to ED+SMNP, but BG18-like memory B cells were rarely detected. Following homologous boosting, BG18-like memory B cells were more frequent in a bolus priming group, but had lower somatic hypermutation and affinities. This outcome was inversely associated with post-prime antibody titers, suggesting antibody feedback can significantly influence rare precursor B cell responses.

immunology↗

bioRxiv2024

HIV-2 evolved ZAP resistance despite increased CpG levels

Simian immunodeficiency viruses infecting sooty mangabeys (SIVsmm) gave rise to nine groups of human immunodeficiency virus type 2 (HIV-2). Two of these (A and B) spread substantially with an estimated 1- 2 million individuals affected. The evolutionary adaptations that facilitated HIV-2s spread in humans are still poorly understood. Here, we report that diverse SIVsmm strains efficiently infect primary human T cells. However, they are more sensitive to interferon than HIV-2, indicating that interferon-stimulated genes (ISGs) pose a barrier to the successful spread of SIVsmm in humans. One of the best-known antiviral ISGs is the zinc finger antiviral protein (ZAP), which targets CpG dinucleotides in RNA. To evade ZAP-mediated restriction, many viruses, including HIV-1, suppress their CpG content. Unexpectedly, we found that HIV-2 is more resistant to ZAP restriction than HIV-1 and SIVsmm despite having 33% more CpGs. Identification of ZAP binding sites using RNA eCLIP and analyses of chimeric HIV-2/SIVsmm viruses, revealed that the determinants of ZAP resistance map to the U3 region of the long-terminal repeat and promote HIV-2 replication in primary human T cells. Our results indicate that ZAP poses a barrier to SIVsmm infection in humans and that HIV-2 evolved a CpG-independent mechanism to evade it.

microbiology↗

bioRxiv2024

Eosinophils protect against SARS-CoV-2 following a vaccine breakthrough infection

Waning immunity and the emergence of immune evasive SARS-CoV-2 variants jeopardize vaccine efficacy leading to breakthrough infections. We have previously shown that innate immune cells play a critical role in controlling SARS-CoV-2. To investigate the innate immune response during breakthrough infections, we modeled breakthrough infections by challenging low-dose vaccinated mice with a vaccine-mismatched SARS-CoV-2 Beta variant. We found that low-dose vaccinated infected mice had a 2-log reduction in lung viral burden, but increased immune cell infiltration in the lung parenchyma, characterized by monocytes, monocyte-derived macrophages, and eosinophils. Single cell RNA-seq revealed viral RNA was highly associated with eosinophils that corresponded to a unique IFN-{gamma} biased signature. Antibody-mediated depletion of eosinophils in vaccinated mice resulted in increased virus replication and dissemination in the lungs, demonstrating that eosinophils in the lungs are protective during SARS-CoV-2 breakthrough infections. These results highlight the critical role for the innate immune response in vaccine mediated protection against SARS-CoV-2.

immunology↗

bioRxiv2024

Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques

The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses ({beta}-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other {beta}-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines. One of these S2-directed mAbs, CC40.8, has demonstrated protective efficacy in small animal models against SARS-CoV-2 challenge. As the next step in the pre-clinical testing of S2-directed antibodies as a strategy to protect from SARS-CoV-2 infection, we evaluated the in vivo efficacy of CC40.8 in a clinically relevant non-human primate model by conducting passive antibody transfer to rhesus macaques (RM) followed by SARS-CoV-2 challenge. CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n=6) of RM, alongside one group that received a control antibody (PGT121). Viral loads in the lower airway were significantly reduced in animals receiving higher doses of CC40.8. We observed a significant reduction in inflammatory cytokines and macrophages within the lower airway of animals infused with 10mg/kg and 1mg/kg doses of CC40.8. Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan-{beta}-CoV vaccines. AUTHOR SUMMARYIn this study, we explore the development of a broadly protective vaccine against betacoronaviruses ({beta}-CoVs), including SARS-CoV-2. We focused on monoclonal antibodies (mAbs) from individuals who recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other {beta}-CoVs. Unlike current vaccines that target the S1 region of the virus, these mAbs target a highly conserved S2 region of the spike protein. One antibody, CC40.8, showed promising results in small animal models. To further test its effectiveness, we infused CC40.8 into rhesus macaques at different doses and then challenged them with SARS-CoV-2. We found that higher doses of CC40.8 significantly reduced viral loads and inflammation in the lower airway. Additionally, there were no escape mutations in the targeted region, suggesting that the virus could not easily evade the antibody. Our findings highlight the potential of S2-targeting antibodies to protect against SARS-CoV-2 and support the development of vaccines that can broadly protect against various {beta}-CoVs. Conflicting InterestsRA, TFR, and DRB are listed as inventors on pending patent applications describing the SARS-CoV-2 and HCoV-HKU1 S cross-reactive antibodies. DRB and RA are listed as inventors on a pending patent application describing the S2 stem epitope immunogens identified in this study. DRB is a consultant for IAVI. All other authors declare that they have no competing interests. ONE SENTENCE SUMMARYPan-beta-coronavirus neutralizing mAb CC40.8 reduces SARS-CoV-2 viral loads and inflammation within the lower airway of infected rhesus macaques and provides pre-clinical support for S2-directed immunization strategies.

immunology↗

bioRxiv2024

Single cell analysis reveals an antiviral network that controls Zika virus infection in human dendritic cells

Zika virus (ZIKV) is a mosquito-borne flavivirus that caused an epidemic in the Americas in 2016 and is linked to severe neonatal birth defects, including microcephaly and spontaneous abortion. To better understand the host response to ZIKV infection, we adapted the 10x Genomics Chromium single cell RNA sequencing (scRNA-seq) assay to simultaneously capture viral RNA and host mRNA. Using this assay, we profiled the antiviral landscape in a population of human moDCs infected with ZIKV at the single cell level. The bystander cells, which lacked detectable viral RNA, expressed an antiviral state that was enriched for genes coinciding predominantly with a type I interferon (IFN) response. Within the infected cells, viral RNA negatively correlated with type I IFN dependent and independent genes (antiviral module). We modeled the ZIKV specific antiviral state at the protein level leveraging experimentally derived protein-interaction data. We identified a highly interconnected network between the antiviral module and other host proteins. In this work, we propose a new paradigm for evaluating the antiviral response to a specific virus, combining an unbiased list of genes that highly correlate with viral RNA on a per cell basis with experimental protein interaction data. Our ZIKV-inclusive scRNA-seq assay will serve as a useful tool to gaining greater insight into the host response to ZIKV and can be applied more broadly to the flavivirus field.

microbiology↗

bioRxiv2023

Integrated longitudinal multi-omics study identifies immune programs associated with COVID-19 severity and mortality in 1152 hospitalized participants

Hospitalized COVID-19 patients exhibit diverse clinical outcomes, with some individuals diverging over time even though their initial disease severity appears similar. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity. In this study, we carried out deep immunophenotyping and conducted longitudinal multi-omics modeling integrating ten distinct assays on a total of 1,152 IMPACC participants and identified several immune cascades that were significant drivers of differential clinical outcomes. Increasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, NETosis, and T-cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma immunoglobulins and B cells, as well as dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to the failure of viral clearance in patients with fatal illness. Our longitudinal multi-omics profiling study revealed novel temporal coordination across diverse omics that potentially explain disease progression, providing insights that inform the targeted development of therapies for hospitalized COVID-19 patients, especially those critically ill.

immunology↗

bioRxiv2022

Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques

Type-I interferons (IFN-I) are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. Here, and for the first time, IFN-I signaling was modulated in rhesus macaques (RMs) prior to and during acute SARS-CoV-2 infection using a mutated IFN2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. In SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. Notably, IFNmod treatment resulted in a potent reduction in (i) SARS-CoV-2 viral load in Bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes; (ii) inflammatory cytokines, chemokines, and CD163+MRC1-inflammatory macrophages in BAL; and (iii) expression of Siglec-1, which enhances SARS-CoV-2 infection and predicts disease severity, on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. This study, using an intervention targeting both IFN- and IFN-{beta} pathways, shows that excessive inflammation driven by type 1 IFN critically contributes to SARS-CoV-2 pathogenesis in RMs, and demonstrates the potential of IFNmod to limit viral replication, SARS-CoV-2 induced inflammation, and COVID-19 severity.

immunology↗

bioRxiv2022

The Vacc-SeqQC Project: Benchmarking RNA-Seq for Clinical Vaccine Studies

Over the last decade, the field of systems vaccinology has emerged, in which high throughput transcriptomics and other omics assays are used to probe changes of the innate and adaptive immune system in response to vaccination. RNA-Seq technology has matured in recent years and is now widely deployed for transcriptional analysis of clinical specimens. The goal of this study was to benchmark technical parameters of RNA-Seq in the context of a multi-site, double-blind randomized clinical trial using primary patient samples. We collected longitudinal peripheral blood mononuclear cell (PBMC) samples from 10 subjects after vaccination with a live attenuated Francisella tularensis vaccine and performed RNA-Seq at two different sites using aliquots from the same sample to generate two large-scale replicate datasets. We evaluated the impact of: (i) filtering lowly-expressed genes, (ii) using external RNA controls, (iii) fold change and false discovery rate (FDR) filtering, (iv) read length, and (v) sequencing depth on differential expressed genes (DEGs) concordance between replicate datasets. Using synthetic mRNA spike-ins, we developed a method for empirically establishing minimal read-count thresholds for maintaining fold change accuracy on a per-experiment basis. We defined a reference PBMC transcriptome by pooling sequence data, and established the impact of read depth and gene filtering on transcript representation. Lastly, we modeled statistical power to detect DE genes for a range of sample sizes, effect sizes, and coverage depths. The results from this study provide RNA sequencing benchmarks and guidelines for planning future similar vaccine studies.

systems biology↗

bioRxiv2021

TREM2+ and interstitial macrophages orchestrate airway inflammation in SARS-CoV-2 infection in rhesus macaques

The COVID-19 pandemic remains a global health crisis, yet, the immunopathological mechanisms driving the development of severe disease remain poorly defined. Here, we utilize a rhesus macaque (RM) model of SARS-CoV-2 infection to delineate perturbations in the innate immune system during acute infection using an integrated systems analysis. We found that SARS-CoV-2 initiated a rapid infiltration (two days post infection) of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and induction of interferon-stimulated genes. At this early interval, we also observed a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generated a novel compendium of RM-specific lung macrophage gene expression using a combination of sc-RNA-Seq data and bulk RNA-Seq of purified populations under steady state conditions. Using these tools, we generated a longitudinal sc-RNA-seq dataset of airway cells in SARS-CoV-2-infected RMs. We identified that SARS-CoV-2 infection elicited a rapid recruitment of two subsets of macrophages into the airway: a C206+MRC1-population resembling murine interstitial macrophages, and a TREM2+ population consistent with CCR2+ infiltrating monocytes, into the alveolar space. These subsets were the predominant source of inflammatory cytokines, accounting for ~75% of IL6 and TNF production, and >90% of IL10 production, whereas the contribution of CD206+MRC+ alveolar macrophages was significantly lower. Treatment of SARS-CoV-2 infected RMs with baricitinib (Olumiant(R)), a novel JAK1/2 inhibitor that recently received Emergency Use Authorization for the treatment of hospitalized COVID-19 patients, was remarkably effective in eliminating the influx of infiltrating, non-alveolar macrophages in the alveolar space, with a concomitant reduction of inflammatory cytokines. This study has delineated the major subsets of lung macrophages driving inflammatory and anti-inflammatory cytokine production within the alveolar space during SARS-CoV-2 infection. One sentence summaryMulti-omic analyses of hyperacute SARS-CoV-2 infection in rhesus macaques identified two population of infiltrating macrophages, as the primary orchestrators of inflammation in the lower airway that can be successfully treated with baricitinib

microbiology↗

bioRxiv2021

CCR2-dependent monocyte-derived cells restrict SARS-CoV-2 infection

SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19) and current evidence suggests severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2-dependent infiltration of monocytes restricts viral burden in the lung. We find that a recently developed mouse-adapted MA-SARS-CoV-2 strain, as well as the emerging B. 1.351 variant, trigger an inflammatory response in the lung characterized by expression of pro-inflammatory cytokines and interferon-stimulated genes. scRNA-seq analysis of lung homogenates identified a hyper-inflammatory monocyte profile. Using intravital antibody labeling, we demonstrate that MA-SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45+ cells into the lung parenchyma that is dominated by monocyte-derived cells. We utilize this model to demonstrate that mechanistically, CCR2 signaling promotes infiltration of classical monocytes into the lung and expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified a CCR2-monocyte axis that is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection.

immunology↗