CD4 T Cell Depletion Exacerbates Acute<i>Mycobacterium tuberculosis</i>While Reactivation of Latent Infection Is Dependent on Severity of Tissue Depletion in Cynomolgus Macaques

Lin, Philana Ling; Rutledge, Tara; Green, Angela M.; Bigbee, Matthew; Fuhrman, Carl R.; Klein, Edwin; Flynn, JoAnne L.

doi:10.1089/aid.2012.0028

Cited by 122 publications

(108 citation statements)

References 45 publications

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“…In contrast, no similar paucibacillary state is observed in standard murine models of Mtb infection. The potential applicability of this finding to understanding human immunity to Mtb is emphasized by the ability of relevant insults to the immune system, such as infection with simian immunodeficiency virus and treatment with tumor necrosis factor-a blocking agents, to induce reactivation TB in macaques with LTBI (33)(34)(35). Despite these clinical similarities, however, our results demonstrate different BAL findings in humans and macaques with LTBI.…”

Section: and Cd11cmentioning

confidence: 70%

Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

Silver

Myers

Jarvela

et al. 2016

Am J Respir Cell Mol Biol

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Immune cells of the distal airways serve as "first responders" of host immunity to the airborne pathogen Mycobacterium tuberculosis (Mtb). Mtb infection of cynomolgus macaques recapitulates the range of human outcomes from clinically silent latent tuberculosis infection (LTBI) to active tuberculosis of various degrees of severity. To further advance the application of this model to human studies, we compared profiles of bronchoalveolar lavage (BAL) cells of humans and cynomolgus macaques before and after Mtb infection. A simple gating strategy effectively defined BAL T-cell and phagocyte populations in both species. BAL from Mtb-naive humans and macaques showed similar differential cell counts. BAL T cells of macaques were composed of fewer CD41 cells but more CD81 and CD4 1 CD8 1 double-positive cells than were BAL T cells of humans. The most common mononuclear phagocyte population in BAL of both species displayed coexpression of HLA-DR, CD206, CD11b, and CD11c; however, multiple phagocyte subsets displaying only some of these markers were observed as well. Macaques with LTBI displayed a marked BAL lymphocytosis that was not observed in humans with LTBI. In macaques, the prevalence of specific mononuclear phagocyte subsets in baseline BAL correlated with ultimate outcomes of Mtb infection (i.e., LTBI versus active disease).Overall, these findings demonstrate the comparability of studies of pulmonary immunity to Mtb in humans and macaques. They also indicate a previously undescribed complexity of airway mononuclear phagocyte populations that suggests further lines of investigation relevant to understanding the mechanisms of both protection from and susceptibility to the development of active tuberculosis within the lung.

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Section: and Cd11cmentioning

confidence: 70%

Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

Silver

Myers

Jarvela

et al. 2016

Am J Respir Cell Mol Biol

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“…The majority of TB studies in NHPs were performed using the Erdman strain (Walsh et al 1996;Langermans et al 2001;Capuano et al 2003;Chen et al 2009;Lin et al 2009;Sharpe et al 2009Sharpe et al , 2010Lin et al 2012cLin et al , 2014, although several used H37Rv (Shen et al 2002b;Gormus et al 2004;Zhang et al 2011;Rayner et al 2013). Although Erdman is generally thought to be more virulent in NHPs, this might not be so clear-cut.…”

Section: Effect Of Inoculum Strain Dose and Routementioning

confidence: 99%

“…þ T cells in maintaining latent TB was explored further in another NHP study in which CD4 þ T cells were depleted from latently infected cynomolgus macaques and reactivation occurred in only half the animals, suggesting that exacerbation of TB following HIV coinfection is not simply caused by the loss of CD4 þ T cells (Lin et al 2012c). Additional studies of macaques with latent TB suggest that SIV coinfection affects CD8 þ T cell and monocyte function, which may be, at least in part, responsible for the TB reactivation (Mattila et al 2011;Diedrich et al 2013).…”

Section: Cells Decline (Lawn and Churchyard 2009) The Role Of Cd4mentioning

confidence: 99%

Modeling Tuberculosis in Nonhuman Primates

Scanga

Flynn

2014

Cold Spring Harbor Perspectives in Medicine

124

115

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Nonhuman primates have emerged as an excellent model of human tuberculosis, in large part because they recapitulate the full spectrum of infection outcome and pathology seen in humans. Several variables inherent to the nonhuman primate models of tuberculosis are discussed in this review, including the monkey species, Mycobacterium tuberculosis strains, and routes of infection, all of which can influence the model to be chosen for various studies. New technologies for studying the microbiology, immunology, and pathogenesis of tuberculosis in nonhuman primates have greatly expanded the capabilities of this model for basic and translational studies, including the development and testing of new treatment and prevention strategies for tuberculosis.

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“…Subsequent studies demonstrated that this cynomolgus macaque model recapitulated the full spectrum of TB encompassing both active disease and latent infection (LTBI) (6). Furthermore, monkeys with LTBI could be reactivated following anti-tumor necrosis factor (anti-TNF) treatment (14), CD4 T cell depletion (15), or simian immunodeficiency virus (SIV) coinfection (16). The Erdman strain has also been used in rhesus and cynomolgus macaques by other research groups (17)(18)(19)(20)(21), and a comparison of BCG vaccination followed by high-dose M. tuberculosis strain Erdman challenge in these two species suggested that cynomolgus macaques had improved control of infection (22).…”

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confidence: 97%

Rhesus Macaques Are More Susceptible to Progressive Tuberculosis than Cynomolgus Macaques: a Quantitative Comparison

et al. 2018

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In the past 2 decades, it has become increasingly clear that nonhuman primates, specifically macaques, are useful models for human tuberculosis (TB). Several macaque species have been used for TB studies, and questions remain about the similarities and differences in TB pathogenesis among macaque species, which can complicate decisions about the best species for a specific experiment. Here we provide a quantitative assessment, using serial positron emission tomography and computed tomography (PET-CT) imaging and precise quantitative determination of bacterial burdens of low-dose Mycobacterium tuberculosis infection in cynomolgus macaques of Chinese origin, rhesus macaques of Chinese origin, and Mauritian cynomolgus macaques. This comprehensive study demonstrates that there is substantial variability in the outcome of infection within and among species. Overall, rhesus macaques have higher rates of disease progression, more lung, lymph node, and extrapulmonary involvement, and higher bacterial burdens than Chinese cynomolgus macaques. The small cohort of Mauritian cynomolgus macaques assessed here indicates that this species is more similar to rhesus macaques than to Chinese cynomolgus macaques in terms of M. tuberculosis infection outcome. These data provide insights into the differences among species, providing valuable data to the field for assessing macaque studies of TB.KEYWORDS Mycobacterium, PET CT, macaque, nonhuman primate, tuberculosis N ovel therapeutics for tuberculosis (TB) are greatly needed to curb the 10.4 million new cases and 1.8 million deaths that occur due to this global pandemic (1). Drugs have aided the fight against TB by saving an estimated 49 million lives between 2000 and 2015 (1). However, the current drug regimen is lengthy and cumbersome, and about 480,000 people developed multidrug-resistant TB in 2015 alone (1), so there is much room for improvement. The only licensed vaccine for TB, Mycobacterium bovis bacillus Calmette-Guérin (BCG), protects infants from severe manifestations of TB but does not provide long-lasting immunity against pulmonary TB (2). The urgent need for new therapeutics for TB has driven the development of novel drugs and vaccines that require preclinical evaluation in animal models. Many animal models are used in TB research, including mice, zebra fish, cattle, rabbits, guinea pigs, and nonhuman primates (NHPs) (3, 4). Mice and NHPs are the two animal models that are the most useful, as the other models suffer from a lack of resources available for immunologic studies. Mice have their shortcomings too, as their TB pathology is not fully representative of the pathology observed in humans, and they do not develop human-like latent TB infection (LTBI). NHPs recapitulate the full spectrum of Mycobacterium tuberculosis

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CD4 T Cell Depletion Exacerbates AcuteMycobacterium tuberculosisWhile Reactivation of Latent Infection Is Dependent on Severity of Tissue Depletion in Cynomolgus Macaques

Cited by 122 publications

References 45 publications

Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

Modeling Tuberculosis in Nonhuman Primates

Rhesus Macaques Are More Susceptible to Progressive Tuberculosis than Cynomolgus Macaques: a Quantitative Comparison

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