Aaron Carmody

National Institute of Allergy and Infectious Diseases

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Kim J. Hasenkrug

National Institute of Allergy and Infectious Diseases

Lara Myers

National Institute of Allergy and Infectious Diseases

Ronald J. Messer

National Institutes of Health

Karin E. Peterson

National Institutes of Health

Atsushi Okumura

National Institute of Allergy and Infectious Diseases

Vincent J. Munster

National Institute of Allergy and Infectious Diseases

Greg Saturday

National Institute of Allergy and Infectious Diseases

Neeltje van Doremalen

National Institute of Allergy and Infectious Diseases

Jonathan E. Schulz

National Institute of Allergy and Infectious Diseases

Sonja M. Best

National Institute of Allergy and Infectious Diseases

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National Institutes of Health

179

National Institute of Allergy and Infectious Diseases

175

Stanford University

Rocky Mountain Research (United States)

Government of the United States of America

Office of Extramural Research

State Key Laboratory of Virology

Global Viral

Montana State University

Rocky Mountain Biological Laboratory

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Old versus young: age-related differences in immune dynamics during SARS-CoV-2 infection in rhesus macaques

Figshare (2021)

Emily Speranza Jyothi N. Purushotham Julia R. Port Benjamin Schwarz Meaghan Flagg

Older age is a key predictor of severe COVID-19. In this study, we utilized the rhesus macaque model to characterize the relationship between age and immune responses to SARS-CoV-2 infection. Two cohorts of eight older (16-23 years) and eight younger (3-5 years) rhesus macaques were inoculated with SARS-CoV-2. Four animals per group were euthanized at 7- and 21-days post inoculation (dpi). Our time-resolved evaluation included viral RNA quantification, clinical observations, pulmonary x-rays, single-cell transcriptomics, multiparameter flow cytometry, multiplex immunohistochemistry, cytokine detection, and lipidomics analysis. Differences in clinical signs, pulmonary infiltrates, and virus replication dynamics were limited between age cohorts. Transcriptional signatures of inflammation-associated genes in cells isolated from bronchoalveolar lavage fluid at 3 dpi revealed efficient mounting of innate immune defenses in both younger and older animals. These findings suggest that age does not substantially skew major outcomes of acute disease in this model. However, age-specific divergence of immune responses emerged during the post-acute phase of infection (7-21 dpi). Older animals exhibited sustained local inflammatory innate responses. Meanwhile, local effector T-cell responses were induced earlier in the younger animals. Circulating lipid mediator and cytokine levels highlighted increased repair-associated signals in the younger animals, contrasted by persistent pro-inflammatory responses in the older animals. In summary, despite similar disease outcomes, multi-omics profiling in SARS-CoV-2-infected rhesus macaques suggests that age may delay or impair the induction of anti-viral cellular immune responses and efficient recouping of homeostasis following acute infection.

Immune escape

Dynamics

10.6084/m9.figshare.16556745

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Validation and Application of a Benchtop Cell Sorter in a Biosafety Level 3 Containment Setting

Applied Biosafety (2021)

Lydia M. Roberts Rebecca L. Anderson Aaron Carmody Catharine M. Bosio

Introduction: Fluorescent-activated cell sorting (FACS) is often the most appropriate technique to obtain pure populations of a cell type of interest for downstream analysis. However, aerosol droplets can be generated during the sort, which poses a biosafety risk when working with samples containing risk group 3 pathogens such as Francisella tularensis, Mycobacterium tuberculosis, Yersinia pestis, and severe acute respiratory syndrome coronavirus 2. For many researchers, placing the equipment required for FACS at biosafety level 3 (BSL-3) is often not possible due to expense, space, or expertise available. Methods: We performed aerosol testing as part of the biosafety evaluation of the MACSQuant Tyto, a completely closed, cartridge-based cell sorter. We also established quality control procedures to routinely evaluate instrument performance. Results: The MACSQuant Tyto does not produce aerosols as part of the sort procedure. Discussion: These data serve as guidance for other facilities with containment laboratories wishing to use the MACSQuant Tyto for cell sorting. Potential users should consult with their Institutional Biosafety Committees to perform in-house risk assessments of this equipment. Conclusion: The MACSQuant Tyto can safely be used on the benchtop to sort samples at BSL-3.

Biosafety

10.1089/apb.20.0065

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Citations (4)

Adaptive immune responses to Zika virus are important for controlling virus infection and preventing infection in brain and testes

The Journal of Immunology (2017)

Clayton W. Winkler Lara Myers Tyson A. Woods Ron J Messer Aaron Carmody

Abstract The recent association between Zika virus (ZIKV) and neurological complications including Guillain-Barré Syndrome (GBS) in adults and CNS abnormalities in fetuses highlights the urgency to understand the immunological mechanisms controlling this emerging infection. Studies have indicated that ZIKV evades the human type I IFN response suggesting a role for the adaptive immune response in resolving infection. However, the inability of ZIKV to antagonize the mouse IFN response renders the virus highly susceptible to circulating IFN in murine models. Thus, as we show here, although wild type C57BL/6 mice mount both cell-mediated and humoral adaptive immune responses to ZIKV, these responses were not required to prevent disease. However, when the type I IFN response of mice was suppressed, then the adaptive immune responses became critical. For example, when type I IFN signaling was blocked by antibodies in Rag1−/− immunodeficient mice, the mice showed dramatic weight loss and ZIKV infection in the brain and testes. This phenotype was not observed in Rag1−/− mice or mice treated with anti-IFNAR alone. Furthermore, we found that the CD8+ T cell responses of pregnant mice to ZIKV infection were diminished compared to non-pregnant mice. It is possible that diminished cell-mediated immunity during pregnancy could increase virus spread to the fetus. These results demonstrate an important role for the adaptive immune response in control of ZIKV infection, and imply that vaccination may prevent ZIKV-related disease, particularly when the type I IFN response is suppressed as it is in humans.

Zika Virus

10.4049/jimmunol.198.supp.122.3

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Journal of Neuroinflammation (2014)

Leah Beth Christensen Tyson A. Woods Aaron Carmody Byron Caughey Karin E. Peterson

The perinatal period is one in which the mammalian brain is particularly vulnerable to immune-mediated damage. Early inflammation in the central nervous system (CNS) is linked with long-term impairment in learning and behavior, necessitating a better understanding of mediators of neuroinflammation. We therefore directly examined how age affected neuroinflammatory responses to pathogenic stimuli.In mice, susceptibility to neurological damage changes dramatically during the first few weeks of life. Accordingly, we compared neuroinflammatory responses to pathogen associated molecular patterns (PAMPs) of neonatal (two day-old) and weanling (21 day-old) mice. Mice were inoculated intracerebrally with PAMPs and the cellular and molecular changes in the neuroinflammatory response were examined.Of the 12 cytokines detected in the CNS following toll-like receptor 4 (TLR4) stimulation, ten were significantly higher in neonates compared with weanling mice. A similar pattern of increased cytokines in neonates was also observed with TLR9 stimulation. Analysis of cellular responses indicated a difference in microglial activation markers in the CNS of neonatal mice and increased expression of proteins known to modulate cellular activation including CD11a, F4/80 and CD172a. We also identified a new marker on microglia, SLAMF7, which was expressed at higher levels in neonates compared with weanlings.A unique neuroinflammatory profile, including higher expression of several proinflammatory cytokines and differential expression of microglial markers, was observed in brain tissue from neonates following TLR stimulation. This increased neuroinflammatory response to PAMPs may explain why the developing brain is particularly sensitive to infection and why infection or stress during this time can lead to long-term damage in the CNS.

Proinflammatory cytokine

Weanling

10.1186/1742-2094-11-70

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Citations (30)

Yersinia pestis Subverts the Dermal Neutrophil Response in a Mouse Model of Bubonic Plague

mBio (2013)

Jeffrey G. Shannon Aaron M. Hasenkrug David W. Dorward Vinod Nair Aaron Carmody

ABSTRACT The majority of human Yersinia pestis infections result from introduction of bacteria into the skin by the bite of an infected flea. Once in the dermis, Y. pestis can evade the host’s innate immune response and subsequently disseminate to the draining lymph node (dLN). There, the pathogen replicates to large numbers, causing the pathognomonic bubo of bubonic plague. In this study, several cytometric and microscopic techniques were used to characterize the early host response to intradermal (i.d.) Y. pestis infection. Mice were infected i.d. with fully virulent or attenuated strains of dsRed-expressing Y. pestis , and tissues were analyzed by flow cytometry. By 4 h postinfection, there were large numbers of neutrophils in the infected dermis and the majority of cell-associated bacteria were associated with neutrophils. We observed a significant effect of the virulence plasmid (pCD1) on bacterial survival and neutrophil activation in the dermis. Intravital microscopy of i.d. Y. pestis infection revealed dynamic interactions between recruited neutrophils and bacteria. In contrast, very few bacteria interacted with dendritic cells (DCs), indicating that this cell type may not play a major role early in Y. pestis infection. Experiments using neutrophil depletion and a CCR7 knockout mouse suggest that dissemination of Y. pestis from the dermis to the dLN is not dependent on neutrophils or DCs. Taken together, the results of this study show a very rapid, robust neutrophil response to Y. pestis in the dermis and that the virulence plasmid pCD1 is important for the evasion of this response. IMPORTANCE Yersinia pestis remains a public health concern today because of sporadic plague outbreaks that occur throughout the world and the potential for its illegitimate use as a bioterrorism weapon. Since bubonic plague pathogenesis is initiated by the introduction of Y. pestis into the skin, we sought to characterize the response of the host’s innate immune cells to bacteria early after intradermal infection. We found that neutrophils, innate immune cells that engulf and destroy microbes, are rapidly recruited to the injection site, irrespective of strain virulence, indicating that Y. pestis is unable to subvert neutrophil recruitment to the site of infection. However, we saw a decreased activation of neutrophils that were associated with Y. pestis strains harboring the pCD1 plasmid, which is essential for virulence. These findings indicate a role for pCD1-encoded factors in suppressing the activation/stimulation of these cells in vivo .

Yersinia pestis

Yersiniosis

10.1128/mbio.00170-13

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Citations (70)

Suppression of Acute Anti-Friend Virus CD8⁺T-Cell Responses by Coinfection with Lactate Dehydrogenase-Elevating Virus

Journal of Virology (2007)

Shelly J. Robertson Christoph G. Ammann Ronald J. Messer Aaron Carmody Lara Myers

Friend virus (FV) and lactate dehydrogenase-elevating virus (LDV) are endemic mouse viruses that can cause long-term chronic infections in mice. We found that numerous mouse-passaged FV isolates also contained LDV and that coinfection with LDV delayed FV-specific CD8(+) T-cell responses during acute infection. While LDV did not alter the type of acute pathology induced by FV, which was severe splenomegaly caused by erythroproliferation, the immunosuppression mediated by LDV increased both the severity and the duration of FV infection. Compared to mice infected with FV alone, those coinfected with both FV and LDV had delayed CD8(+) T-cell responses, as measured by FV-specific tetramers. This delayed response accounted for the prolonged and exacerbated acute phase of FV infection. Suppression of FV-specific CD8(+) T-cell responses occurred not only in mice infected concomitantly with LDV but also in mice chronically infected with LDV 8 weeks prior to infection with FV. The LDV-induced suppression was not mediated by T regulatory cells, and no inhibition of the CD4(+) T-cell or antibody responses was observed. Considering that most human adults are carriers of chronically infectious viruses at the time of new virus insults and that coinfections with viruses such as human immunodeficiency virus and hepatitis C virus are currently epidemic, it is of great interest to determine how infection with one virus may impact host responses to a second infection. Coinfection of mice with LDV and FV provides a well-defined, natural host model for such studies.

Chronic infection

10.1128/jvi.01413-07

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Citations (78)

Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity

Nature (2024)

Jason Ross Lara Myers Joseph J. Noh Madison M. Collins Aaron Carmody

Lymphopoiesis

10.1038/s41586-024-07238-x

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CD8+ T-cells target the Crimean-Congo haemorrhagic fever virus Gc protein to control the infection in wild-type mice

EBioMedicine (2023)

Deepashri Rao Kimberly Meade‐White Shanna Leventhal Evan A. Mihalakakos Aaron Carmody

Crimean-Congo haemorrhagic fever (CCHF) is a serious viral hemorrhagic fever caused by the CCHF virus (CCHFV). Spread by the bites of infected ticks or handling of viremic livestock, human disease is characterized by a non-specific febrile illness that can rapidly progress to fatal hemorrhagic disease. No vaccines or antivirals are available. Case fatality rates can vary but can be higher than 30%, although sub-clinical infections are often unrecognized and unreported. Yet, while most humans infected with CCHFV will survive the infection, often with little-to-no symptoms, the host responses that control the infection are unknown.Here we investigated the role of cellular immunity in control of CCHFV infection in an immunocompetent mouse model.We found that CD8+ T-cells are crucial for efficient control of the acute infection and rapidly acquired CCHFV-specific antiviral effector functions such as production of antiviral cytokines and degranulating in response to CCHFV peptides. We further identified the minimal CD8+ T-cell epitopes in the viral Gc proteins and that infection of mice lacking IFNγ resulted in worsened disease and higher viral loads.Together our data suggest that CD8+ T-cells are important for control of acute CCHFV infection likely through production of antiviral cytokines.This work was supported by the Intramural Research Program of the NIH.

10.1016/j.ebiom.2023.104839

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T cell correlates of solid protective immunity following immunization of macaques with a live-attenuated trachoma vaccine (P4403)

The Journal of Immunology (2013)

Harlan D. Caldwell Norma Olivares-Zavaleta Aaron Carmody Bill Whitmire Laszlo Kari

Abstract Trachoma, caused by Chlamydia trachomatis, is the world’s leading cause of preventable blindness for which a vaccine is needed. We previously described a live-attenuated trachoma vaccine (LATV) in non-human primates (Kari L. 2011 JEM 208: 2217-23). Vaccinated macaques were either solidly or partially protected following challenge with virulent trachoma organisms. Our current goal was to characterize immune responses that correlated with solid protective immunity. Here, we preformed intramuscular boosting of LATV vaccinated macaques and studied the T cell recall response in PBMC by flow cytometry. Both solidly and partially protected macaques exhibited a strong PBMC CD8+ T recall response following intramuscular immunization. Notably, however; only CD8+ T cells from solidly protected macaques strongly proliferated in response to chlamydial soluble antigen (SA) prepared from chlamydial infected cells. The SA contained proteins known to be secreted by chlamydiae into the host cytosol making them logical antigenic targets of cytotoxic CD8+ T cells. The SA expanded CD8+ T cells expressed IFN-γ, granzyme B, and α4β7 integrin implicating them as effectors important to the development of solid protective immunity at the ocular mucosae. Identifying the effector function and antigens recognized by these CD8+ T cells will be the focus of future studies as this information will provide insights into the design of more conventional immunotherapeutic approaches for trachoma control.

Attenuated vaccine

10.4049/jimmunol.190.supp.205.11

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Visualization of Spirochetes by Labeling Membrane Proteins With Fluorescent Biarsenical Dyes

Frontiers in Cellular and Infection Microbiology (2019)

Chadwick Hillman Philip E. Stewart Martin Strnad Hunter H. Stone Tregei Starr

Numerous methods exist for fluorescently labeling proteins either as direct fusion proteins (GFP, RFP, YFP, etc. - attached to the protein of interest) or utilizing accessory proteins to produce fluorescence (SNAP-tag, CLIP-tag), but the significant increase in size that these accompanying proteins add may hinder or impede proper protein folding, cellular localization, or oligomerization. Fluorescently labeling proteins with biarsenical dyes, like FlAsH, circumvents this issue by using a short 6-amino acid tetracysteine motif that binds the membrane-permeable dye and allows visualization of living cells. Here, we report the successful adaptation of FlAsH dye for live-cell imaging of two genera of spirochetes, Leptospira and Borrelia, by labeling inner or outer membrane proteins tagged with tetracysteine motifs. Visualization of labeled spirochetes was possible by fluorescence microscopy and flow cytometry. A subsequent increase in fluorescent signal intensity, including prolonged detection, was achieved by concatenating two copies of the 6-amino acid motif. Overall, we demonstrate several positive attributes of the biarsenical dye system in that the technique is broadly applicable across spirochete genera, the tetracysteine motif is stably retained and does not interfere with protein function throughout the B. burgdorferi infectious cycle, and the membrane-permeable nature of the dyes permits fluorescent detection of proteins in different cellular locations without the need for fixation or permeabilization. Using this method, new avenues of investigation into spirochete morphology and motility, previously inaccessible with large fluorescent proteins, can now be explored.

10.3389/fcimb.2019.00287

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Citations (9)