bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of vaccine-induced mucosal NKp44+ and mucosal NKp44−NKG2A− cells on SIVinfection outcomes in rhesus macaques
Authors: RAHMAN MOHAMMAD ARIF , Ko Eunju , Enyindah-Asonye Gospel , Hait Sabrina Helmold , Hoang Tanya , Robert-Guroff Marjorie 
Published: January 2023

Abstract
NK cells play an essential role in control of viral infection. We investigated NK cell dynamics and function post-vaccination with replicating adenovirus (Ad)-SIV recombinants and SIV envelope and subsequent intravaginal exposure to SIV. Macaques that became infected were studied. As no differences in NK cell frequencies or cytokine production were seen between vaccinated and Ad-empty/alum controls, suggesting responses observed were due to the Ad-vector and alum immunizations, the groups were combined. Mucosal NKp44+ NK cells increased post-vaccination and returned to pre-levels post-infection. Post-vaccination NKp44+ cell frequencies tended to correlate (p = 0.070, r = 0.683) while NKp44+IL-17+ cell frequencies positively correlated (p = 0.042, r = 0.742) with number of challenges for SIV acquisition. Additionally, negative correlations with peak viral load (VL) (p = 0.0072, r = −0.881) and chronic median VL (p = 0.0107, r = −0.857) suggested that these IL-17+ cells might inhibit SIV acquisition by promoting epithelial integrity and mucosal homeostasis. In contrast, the frequency of NKp44−NKG2A−double negative (DN) cells, a less-defined innate lymphoid cell population, decreased post-vaccination, but returned to pre-level post-infection. Post-vaccination DN cells (p = 0.042, r = −0.743) and IFN- γ+DN cells (p = 0.038, r = −0.755) negatively correlated with number of SIV challenges and positively correlated with chronic median VL (p = 0.046, r = 0.738) and peak VL (p = 0.001, r = 0.952), suggesting both cell populations might enhance SIV acquisition and contribute to viremia. No associations of circulating NK cells with protection were seen. Vaccines that promote mucosal NKp44+ cells and suppress DN cells are likely desirable.
Antibody cross-reactivity in chronic HIV/HCV co-infection
Authors: Pilewski Kelsey , Setliff Ian , Kalams Spyros , Georgiev Ivelin 
Published: January 2023

Abstract
HIV/HCV co-infected individuals fair worse than their mono-infected counterparts, experiencing rapid progression to fibrosis, and increased chance of liver damage due to HAART. Given this, novel antibody therapeutic and rational vaccine design for both viruses have become top priorities worldwide. This study seeks to understand the antibody response in chronic HIV/HCV co-infection. Normally selected against, antibodies that recognize diverse antigens confer a selective advantage against highly mutable pathogens, such as HIV and HCV. We hypothesized that chronic co-infection leads to the development of antibodies that can recognize both viruses.
In collaboration with the Vanderbilt HIV cohort, we obtained patient PBMCs from a single HIV/HCV co-infected African American man, at four timepoints between 0.5 – 3 years post HIV infection (ypi). For 0.5, and 1.5 ypi we performed antigen-specific B cell sorting and deep B cell receptor sequencing. Notably, we used fluorescently-labeled envelope proteins from each virus to isolate virus-specific B cells from infected peripheral blood. We identified multiple unique B cells positive for both HIV and HCV antigens, which we then expressed as recombinant antibodies to characterize. Intriguingly, we see antibody-mediated neutralization of diverse viral strains, suggesting a common mode of antiviral protection. Matching single cell sequencing and functional to next-generation sequencing data allows for powerful delineation and characterization of virus-specific antibody responses. Furthermore, this study presents the first evidence of antibody cross-reactivity between genetically unrelated viruses, which could have great impact on future vaccine design efforts.
Reprogramming the antigen specificity of B cells using genome-editing technologies
Authors: Gonzalez-Martin Alicia , Andrabi Raiees , Fuller Roberta P. , Murrell Ben , McCoy Laura E. , Porter Katelyn , Huang Deli , Li Wenjuan , Sok Devin , Le Khoa , Briney Bryan , Chateau Morgan , Rogers Geoffrey , Hangartner Lars , Feeney Ann J. , Nemazee David , Cannon Paula , Burton Dennis , Voss James E. 
Published: January 2023

Abstract
HIV infection is a global health concern affecting roughly 37 million people and still no effective vaccine is available for prevention. While rare, HIV broadly neutralizing antibodies (bnAbs) have been isolated from patients. These antibodies have been shown to be protective in animal models if present at the time of challenge in passive transfer experiments. Thus, elicitation of HIV bnAbs is a central goal for vaccine design. These antibodies, however, contain rare features not present in the naïve human antibody repertoire. We have developed a universal genome editing strategy to introduce novel paratopes into the human repertoire. We used CRISPR-Cas9 in a homology directed repair strategy, to replace the heavy chain (HC) variable region in B cell lines and human primary B cells with that from an HIV broadly neutralizing antibody, PG9. The modified locus expresses PG9 HC which pairs with native light chains resulting in the cell surface expression of HIV specific BCRs. The engineered B cells are subject to class switch recombination and somatic hypermutation to generate HIV-specific BCRs with improved neutralizing breath and potency.
Evolution of the AID/APOBEC family of cytidine deaminases in lampreys
Authors: Hirano Masayuki , Sutoh Yoichi , Das Sabyasachi , Cooper Max 
Published: January 2023

Abstract
Jawless vertebrates, lampreys and hagfish, have antigen receptors termed variable lymphocyte receptors (VLRs), which are composed of leucine-rich repeat (LRR) segments. Three types of VLR genes, VLRA, VLRB and VLRC, are somatically assembled in lymphocytes by a gene conversion-like process. In this process, flanking LRR gene cassettes are randomly and sequentially incorporated in a piece-wise fashion into an incomplete germline VLR gene to generate mature VLR genes.
Activation-induced cytidine deaminase (AID), a member of AID/APOBEC family of cytidine deaminases (CDAs), is a well-known contributor to antigen receptor diversification in jawed vertebrates. We have only limited information about the molecular basis for the assembly and diversification of VLR genes in jawless vertebrates. Two AID/APOBEC-type CDAs, CDA1 and CDA2, have been reported in lampreys. We have previously shown that CDA1 is expressed in VLRA+ and VLRC+ lymphocytes, whereas the CDA2 is expressed in VLRB+ lymphocytes. VLRA and VLRC gene assembly coincide with expression of CDA1 in the gill tip region displaying thymus-equivalent features. Although CDA1 has been shown to induce C to U mutations in bacterial and yeast DNA, mutational activity of CDA2 has not been reported. To find molecules for VLRB gene assembly, we have searched the lamprey genomic database and our transcriptome data from lamprey lymphocytes, and have identified four splice variants of CDA2. Gene expression analysis indicated that all CDA2 splice variants are expressed only in VLRB+ cells. We also found that some of the CDA2 splice variants have AID-like mutational activity in the in vitro system. These results suggest the function and regulation of CDA2 splice variants in VLRB+ cells.
Somatic hypermutation of T cell receptor gamma, delta, and beta chains in nurse sharks
Authors: Ott Jeannine A , Harrison Jenna , Ota Yuko , Flajnik Martin F , Criscitiello Michael F 
Published: January 2023

Abstract
Many γδ T cells typically bind antigen in a manner similar to that of immunoglobulins, recognizing and directly binding small molecules and intact proteins without presentation by classical MHC:Ag complexes. In this way, γδ T cells combine an innate-like immune response with an adaptive recognition strategy, providing both an immediate response to pathogen invasion and an ongoing, adaptive response to inflammation. However, γδ T cells often recombine tissue-specific, restricted sets of genes that have limited junctional diversity. Thus, somatic hypermutation (SHM) presents a useful solution for diversifying these antibody-like T cell receptors (TCR) by fine-tuning ligand recognition or permitting changes within the loci that allow receptors to evolve more rapidly to changing ligand environments. In fact, recent studies in sandbar shark have confirmed definitively that the γ chain locus of γδ T cells employs SHM as a mechanism to generate more diverse γδ TCR, and follow-up studies in dromedary camel indicated that loci of both γ and δ chains use SHM to diversify γδ TCR. In nurse sharks, we found evidence that SHM acts in the thymus, altering the α chain locus of αβ T cells to broaden the primary αβ T cell repertoire. Further, early results suggest that SHM modifies both γ and δ chain loci (but not β chain locus of αβ T cells) and this alteration may occur in the thymus, indicating that this receptor fine-tuning may precede ligand recognition.
CD8+ T Cells require IL-27R for optimal generation of an effector response during influenza infection
Authors: Dunbar Paul , Li Zheng-Rong Tiger , Lobby Jenna , Hayward Sarah L , Lawrence Laurel , Kohlmeier Jacob E 
Published: January 2023

Abstract
Previous reports have demonstrated the many effects of IL-27 on CD4 T cell activation and differentiation, in addition to a role for IL-27 in cancer therapies mediated by cytolytic CD8 T cells. However, as IL-27 is produced by many cell types during infection, and the IL-27 receptor (IL-27R) is widely expressed on NK cells, as well as on activated CD4 and CD8 T cells, the direct effects of IL-27 signaling on CD8 T cell function are less well understood. We used a murine model of influenza infection in combination with co-transfer of congenic wild type (WT) and IL-27R−/− OT-I CD8 T cells to investigate whether IL-27 signaling had a direct effect on virus-specific CD8 T cell function in vivo. We observed a dramatic reduction in the frequency and number of IL-27R−/− OT-I compared to their WT OT-I counterparts within the same host following influenza infection, indicating a CD8 T cell-intrinsic role for IL-27 in the generation of an acute anti-viral response. This defect was observed in the spleen, lung interstitium, airways and the lung-draining mediastinal lymph node, indicating a systemic defect in development of the CD8 T cell effector response in the absence of IL-27R signaling. Both memory precursor and short lived effector cells were reduced in the absence of IL-27R signaling indicating potential defects in both effector and memory generation. We are currently exploring the mechanism of defective effector CD8 T cell generation in the absence of cell-intrinsic IL-27R signaling. Overall, these findings show a cell-intrinsic role for IL-27 signaling in the generation of a robust effector CD8 T cell response following influenza infection.
The Nonlinear Relations that Predict Influenza Viral Dynamics, Host Response, Pathology, and Disease Severity
Authors: Smith Amber M 
Published: January 2023

Abstract
Influenza A viruses cause a significant amount of morbidity and mortality. Understanding how the infection is controlled by host immune responses and how different factors influence severity are critical to combat the infection. During infection, virus increases exponentially, peaks, then declines until resolution. The viral decline is often biphasic, which we previously determined is a consequence of density-dependent infected cell clearance. The second, rapid clearance phase corresponds with the infiltration of CD8 T cells, but how the rate changes with infected cell density and CD8 density is unclear. Further, neither of these kinetics directly correlate to disease severity. Thus, we investigated these relations by infecting mice with influenza A/PR8, simultaneously measuring virus and CD8s, and developing/calibrating a kinetic model. The model predicts that virus resolution is sensitive to T cell expansion, that there is a critical CD8 magnitude below which the infection is significantly prolonged, and that the efficiency of CD8-mediated clearance is dependent on infected cell density. To further examine this finding and validate the model, we quantified infected cells kinetics using histomorphometry. These data showed that the area of lung infected reflects the predicted infected cell dynamics, and that the infection resolution dynamics parallel the relative CD8 magnitude. Our analysis further revealed a nonlinear relation between disease severity and the percent damaged lung. Establishing these critical connections that map the kinetics of virus, infected cells, T cells, lung pathology, and disease severity aids our ability to predict the course of infection, disease progression, and potential complications.
Influenza virus M1 interacts with SLD5 to block host cell cycle and inhibit lung epithelial regeneration
Authors: Fang Min , Zhu Li , Zhao Wenming 
Published: January 2023

Abstract
Influenza virus matrix 1 protein (M1) is highly conserved and plays essential roles at many stages of virus life cycle. Here we used a yeast two-hybrid system to identify the host protein SLD5, a component of the GINS complex, which is essential for the initiation of DNA replication in eukaryotic cells, as a new M1 interacting protein. M1 from several different influenza virus strains all interacted with SLD5. Overexpression of SLD5 inhibited influenza virus replication. Transient, stable or inducible expression of M1 induced host cell cycle blockade at G0/G1 phase. Importantly, SLD5 partly rescued M1 expression- or influenza virus infection-induced G0/G1 phase accumulation in cell lines and primary mouse embryonic fibroblasts. Importantly, SLD5 transgenic mice exhibited higher resistance and improved lung epithelial regeneration after virus infection compared to wild type mice. Therefore, influenza virus M1 inhibits host cell cycle process by interacting with SLD5. Our finding reveals the multifunctional nature of M1 and provides new insight for understanding influenza virus-host interaction.
BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza infection
Authors: Sun Jie , Zhu Bibo 
Published: January 2023

Abstract
B-cell lymphoma 6 (BCL6) is a transcriptional repressor that is best known for its pivotal function in governing follicular T helper cell and germinal center B cell responses. However, its role in innate anti-viral responses is only now being appreciated. Here we find that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza infection, which was independent of IFNAR1 signaling. In contrary to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or macrophages, attenuated host inflammation and morbidity following influenza infection. Mechanistically, BCL6 disruption resulted in increased expression of a number of genes involved in cellular apoptosis in neutrophils. Consequently, BCL6 deficiency promoted neutrophil apoptosis, specifically at the site of infection. Furthermore, partial neutrophil depletion leaded to diminished pulmonary inflammation and decreased host morbidity. Our results have revealed a previously unappreciated role of BCL6 in modulating neutrophil function and apoptosis at the infected lungs for the regulation of host disease development following influenza infection. Furthermore, our studies indicate that neutrophil survival is tightly regulated in a tissue-specific fashion, thereby influencing inflammation and immunopathology development during acute respiratory viral infection.
Patrolling ILCs restrain mucosal viral replication through tissue-wide delivery of IFN-γ
Authors: Shannon John P , Reynoso Glennys V. , Kamenyeva Olena , McManus Daniel T , Hickman Heather D. 
Published: January 2023

Abstract
Smallpox, caused by infection with variola virus, led to devastating human pandemics with high mortality until eradication through a global vaccination campaign. Despite eradication, the precise immune mechanisms underlying recovery from infection are incompletely understood. The most common model employed to study smallpox is murine infection with vaccinia virus (VACV), the virus used for human smallpox vaccination. VACV models of smallpox infection commonly employ intranasal or even intravenous routes of infection, with both resulting in widespread viral dissemination. However, variola virus infected humans through the oropharyngeal mucosa, after which oral lesions developed and ruptured, spilling copious infectious virus into the saliva (the route of human-to-human spread). To understand protection in this critical barrier site, we developed a mouse model of lip (labial mucosal) infection. After labial administration, VACV replicates to high titers and two waves of group I innate lymphoid cells (ILCs) are recruited in response to infection. Intravital imaging revealed highly mobile ILCs in the oral mucosa, most of which failed to contact virus-infected cells. Despite the lack of stable contacts, depletion of NK1.1+ cells enhanced viral replication and spread. Instead, ILCs delivered IFN-γ to the mucosal tissue, inducing an antiviral signature in the epithelium. Together, these data illustrate the complex nature of immune protection in a critical yet overlooked tissue during viral pathogenesis.
Interferon-α producing dendritic cells impair viremia control in simian immunodeficiency virus-infected rhesus macaques
Authors: Ko Eunju , Hait Sabrina Helmold , Rahman Mohammad Arif , Enyindah-Asonye Gospel , Hogge Christopher James , Hoang Tanya , Robert-Guroff Marjorie 
Published: January 2023

Abstract
Dendritic cells (DCs) are potent antigen-presenting cells that orchestrate innate and adaptive immune responses. Interferon (IFN)-α, a cytokine produced by DCs, has both protective and detrimental activities in viral infection. Here we assessed the phenotypes and IFN-α production of mucosal and circulatory DCs in simian immunodeficiency virus (SIV)-infected rhesus macaques during acute and chronic infection to determine their contribution to viremia control. Macaques were initially vaccinated with replicating adenovirus-SIV recombinants, boosted with SIV envelope, and exposed to SIV intravaginally. Those that became infected were divided into high (HVL) and low viral load (LVL) groups based on plasma viremia at 12 weeks post-infection. HVL macaques had ≥ 7.98×104 SIV RNA copies/ml plasma; LVL animals had ≤ 1.17×104. Immunizations increased rectal plasmacytoid DCs (pDCs, CD123+, p=0.0039 in HVL), but SIV infection induced loss of rectal pDCs in the acute (p=0.0039) and chronic phases (p=0.0078). Blood myeloid DCs (mDCs, CD11c+) were increased in the chronic phase (p=0.0195). No differences in HVL and LVL DC frequencies were seen during SIV infection. But higher blood IFN-α+pDCs and mDCs in the acute phase were observed in HVL compared to LVL animals (p=0.042 in both pDCs and mDCs), suggesting blood IFN-α might contribute to SIV persistence and interrupt viremia control. Chronic IFN-α+ rectal pDCs (p=0.015) and acute IFN-α+ blood pDCs (p=0.032) and mDCs (p=0.0058) positively correlated with peak plasma VLs implying IFN-α lessened viral control in SIV infection. Our data suggest that elevated IFN-α+ DC frequencies in acute SIV infection impair SIV viremia control and help maintain higher VLs in SIV-infected rhesus macaques.
CD5+ B-1 cell responses to infection are facilitated by toll-like receptor stimulation
Authors: Smith Fauna Leah , Savage Hannah Pritikin , Kläsener Kathrin , Reth Michael , Baumgarth Nicole 
Published: January 2023

Abstract
B-1 lymphocytes are neonatally-derived, self-reactive, innate-like B cells that produce natural IgM at steady state. B-1 cells also actively respond to infections with induced local IgM production. These two distinct functions of B-1 cells have been linked to the expression CD5, an inhibitor of BCR signaling, with CD5+ cells thought to contribute to steady state IgM, and CD5− cells to local IgM production during infection. The mechanisms underlying such “division of labor” are poorly understood. We aim to test our hypothesis that CD5+ B-1 cells are stimulated by innate signals via TLR, during infection, resulting in their activation and differentiation into CD5− IgM antibody-secreting cells. For that we first cultured CD5+ B-1 cells with TLR9 agonist, ODN-CpG. The cells proliferated, secreted IgM and showed increased Nur77 expression, Akt phosphorylation and interaction of Syk with CD79a, signs of BCR signaling. They lost expression of the BCR-inhibitor CD5 and upregulated the plasma cell marker CD138+. Following influenza infection of mice, CD5+ B-1 cells migrated to the mediastinal lymph nodes (medLN) where they lost CD5 and became IgM secreting cells. Both, global TLR−/− mice and chimeric mice lacking TLR only on B-1 cells had reduced numbers of B-1 derived plasma cells and antibody secreting cells in the medLN compared to controls. Our findings show that TLR-mediated activation of CD5+ B-1 cells results in the rapid reorganization of the BCR-complex, followed by loss of CD5 and that TLR stimulation of CD5+ B-1 is required for differentiation of B-1 cells to infection in vivo. Overall our data suggest that CD5+ and CD5− B-1 cells are not distinct subsets, but rather that CD5 expression indicates the activation state of B-1 cells.
Regulation of antiviral CD8 T cell immunity by CD352/SLAMF6: from patterns to pathways
Authors: van der Heide Verena , Homann Dirk 
Published: January 2023

Abstract
A better understanding of CD8 memory T cell (TM) formation during acute and chronic viral infections is critical for both effective immunotherapy and vaccine design. Signaling lymphocytic activation molecule family receptors (SLAMF) including CD150, CD48, CD229, CD244, CD84, CD352, and CD319 were found to be involved in T cell activation and differentiation, but their contribution to the regulation of antigen-specific T cell immunity remains incompletely understood. Here, we analyzed the dynamics of SLAMF co-expression patterns by antiviral CD8 T cells in response to acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. Our results demonstrate distinct SLAMF levels not only on LCMV-specific CD8 effector (TE) and TM cell subsets, but differential kinetics during acute vs. chronic infection. Importantly, we identified CD352 as a unique marker for long-term CD8 TM potential and capacity with significant upregulation on memory-precursor (MPEC) vs. short-lived effector (SLEC) as well as on central (TCM) vs. effector memory (TEM) CD8 T cells (MPEC&gt;&gt;TCM&gt;TEM≥SLEC). Moreover, in the context of chronic viral infection, we found CD352+ CD8 T cells to be partially resistant to exhaustion as demonstrated by a memory-like phenotype, preserved CD8 T cell function, and better in vivo recall capacity upon adoptive transfer into naïve hosts. Conversely, chronically-infected CD352-deficient mice showed an impaired CD8 T cell response with reduced frequencies of LCMV-specific CD8 T cells, a more exhausted phenotype, lower expression of TM markers, and reduced functional properties. Collectively, our data reveal CD352 as a potential therapeutic target to modify CD8 T cell responses during acute and chronic viral infections.