Ultra-low Dose Aerosol Infection of Mice with Mycobacterium tuberculosis More Closely Models Human Tuberculosis

Plumlee, Courtney R.; Duffy, Fergal J.; Gern, Benjamin H.; Delahaye, Jared L.; Cohen, Sara; Stoltzfus, Caleb; Rustad, Tige R.; Hansen, Scott G.; Axthelm, Michael K.; Picker, Louis J.; Aitchison, John D.; Sherman, David R.; Ganusov, Vitaly V.; Gerner, Michael Y.; Zak, Daniel E.; Urdahl, Kevin B.

doi:10.1016/j.chom.2020.10.003

Cited by 81 publications

(94 citation statements)

References 73 publications

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“…We have included the dose, Mtb strain and route of infection per experiment. Mtb can establish an infection via the lungs with just a few bacilli ( 156 , 157 ), and therefore models using large doses and atypical routes may represent different aspects of Mtb disease but not necessarily follow the normal mode of infection. The magnitude of disease in mice also changes with the strain of Mtb , where for example the H37Rv strain is expected to be less virulent than the related Erdman strain and the HN878 strain.…”

Section: Consequences Of Prr Kos In Micementioning

confidence: 99%

Underwhelming or Misunderstood? Genetic Variability of Pattern Recognition Receptors in Immune Responses and Resistance to Mycobacterium tuberculosis

et al. 2021

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Human genetic control is thought to affect a considerable part of the outcome of infection with Mycobacterium tuberculosis (Mtb). Most of us deal with the pathogen by containment (associated with clinical “latency”) or sterilization, but tragically millions each year do not. After decades of studies on host genetic susceptibility to Mtb infection, genetic variation has been discovered to play a role in tuberculous immunoreactivity and tuberculosis (TB) disease. Genes encoding pattern recognition receptors (PRRs) enable a consistent, molecularly direct interaction between humans and Mtb which suggests the potential for co-evolution. In this review, we explore the roles ascribed to PRRs during Mtb infection and ask whether such a longstanding and intimate interface between our immune system and this pathogen plays a critical role in determining the outcome of Mtb infection. The scientific evidence to date suggests that PRR variation is clearly implicated in altered immunity to Mtb but has a more subtle role in limiting the pathogen and pathogenesis. In contrast to ‘effectors’ like IFN-γ, IL-12, Nitric Oxide and TNF that are critical for Mtb control, ‘sensors’ like PRRs are less critical for the outcome of Mtb infection. This is potentially due to redundancy of the numerous PRRs in the innate arsenal, such that Mtb rarely goes unnoticed. Genetic association studies investigating PRRs during Mtb infection should therefore be designed to investigate endophenotypes of infection – such as immunological or clinical variation – rather than just TB disease, if we hope to understand the molecular interface between innate immunity and Mtb.

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Section: Consequences Of Prr Kos In Micementioning

confidence: 99%

Underwhelming or Misunderstood? Genetic Variability of Pattern Recognition Receptors in Immune Responses and Resistance to Mycobacterium tuberculosis

et al. 2021

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“…Multiplexed imaging and spatially resolved sequencing technologies have revealed complex cellular organization across tissue types and diverse pathological conditions (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Advanced computational and statistical approaches applied to such datasets allow quantification of various spatial properties, such as cellular distance relationships, preferential cell-cell associations, and organization of tissue microenvironments (16,(20)(21)(22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Multi-Parameter Quantitative Imaging of Tumor Microenvironments Reveals Perivascular Immune Niches Associated With Anti-Tumor Immunity

et al. 2021

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Tumors are populated by a multitude of immune cell types with varied phenotypic and functional properties, which can either promote or inhibit anti-tumor responses. Appropriate localization and function of these cells within tumors is critical for protective immunity, with CD8 T cell infiltration being a biomarker of disease outcome and therapeutic efficacy. Recent multiplexed imaging approaches have revealed highly complex patterns of localization for these immune cell subsets and the generation of distinct tumor microenvironments (TMEs), which can vary among cancer types, individuals, and within individual tumors. While it is recognized that TMEs play a pivotal role in disease progression, a better understanding of their composition, organization, and heterogeneity, as well as how distinct TMEs are reshaped with immunotherapy, is necessary. Here, we performed spatial analysis using multi-parameter confocal imaging, histocytometry, and CytoMAP to study the microanatomical organization of immune cells in two widely used preclinical cancer models, the MC38 colorectal and KPC pancreatic murine tumors engineered to express human carcinoembryonic antigen (CEA). Immune responses were examined in either unperturbed tumors or after immunotherapy with a CEA T cell bispecific (CEA-TCB) surrogate antibody and anti-PD-L1 treatment. CEA-TCB mono and combination immunotherapy markedly enhanced intra-tumoral cellularity of CD8 T cells, dominantly driven by the expansion of TCF1-PD1+ effector T cells and with more minor increases in TCF1+PD1+ resource CD8 T cells. The majority of infiltrating T cells, particularly resource CD8 T cells, were colocalized with dendritic cells (DCs) or activated MHCII+ macrophages, but largely avoided the deeper tumor nest regions composed of cancer cells and non-activated macrophages. These myeloid cell – T cell aggregates were found in close proximity to tumor blood vessels, generating perivascular immune niches. This perivascular TME was present in untreated samples and markedly increased after CEA-TCB therapy, with its relative abundance positively associated with response to therapy. Together, these studies demonstrate the utility of advanced spatial analysis in cancer research by revealing that blood vessels are key organizational hubs of innate and adaptive immune cells within tumors, and suggesting the likely relevance of the perivascular immune TME in disease outcome.

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“…Development of effective TB vaccines requires innovative approaches and insights into biological mechanisms that confer protection and/or lead to disease. Michael Gerner (University of Washington, USA) presented insights from the ultra-low dose aerosol Mycobacterium tuberculosis ( Mtb ) infection model in mice [5] , which recapitulates human lung granuloma composition better than mice infected with a conventional high dose. Using this model coupled with multiplex confocal imaging and quantitative spatial analysis with histo-cytometry and CytoMAP, his group showed that Transforming Growth Factor β (TGF-β) signaling restricted Mtb -specific T cell responses in the lung parenchyma resulting in impaired Mtb containment in the murine granuloma [6] .…”

Section: Novel Insights and Approaches To Tb Vaccine Randdmentioning

confidence: 99%

Meeting report: Virtual Global Forum on Tuberculosis Vaccines, 20–22 April 2021

Suliman¹,

Pelzer²,

Shaku³

et al. 2021

Vaccine

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The Global Forum on Tuberculosis (TB) Vaccines was held virtually from 20 to 22 April 2021, marking its 20 th anniversary. The Global Forum on TB Vaccines is the world's largest gathering of stakeholders striving to develop new vaccines to prevent TB. The program included more than 60 speakers in 11 scientific sessions, panel discussions, and workshops. It provided an overview of the state of the field, and an opportunity to share the latest research findings, as well as new and innovative approaches to TB vaccine research and development (R&D). This year, it was held against the backdrop of the COVID-19 pandemic and convened researchers, developers, funders, and other stakeholders remotely to discuss opportunities and challenges for TB vaccine R&D in these unprecedented times.

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Ultra-low Dose Aerosol Infection of Mice with Mycobacterium tuberculosis More Closely Models Human Tuberculosis

Cited by 81 publications

References 73 publications

Underwhelming or Misunderstood? Genetic Variability of Pattern Recognition Receptors in Immune Responses and Resistance to Mycobacterium tuberculosis

Underwhelming or Misunderstood? Genetic Variability of Pattern Recognition Receptors in Immune Responses and Resistance to Mycobacterium tuberculosis

Multi-Parameter Quantitative Imaging of Tumor Microenvironments Reveals Perivascular Immune Niches Associated With Anti-Tumor Immunity

Meeting report: Virtual Global Forum on Tuberculosis Vaccines, 20–22 April 2021

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