Publications

2019

Lafuse, W. P., M. V. S. Rajaram, Q. Wu, J. I. Moliva, J. B. Torrelles, J. Turner, and L. S. Schlesinger. 2019. “Identification of an Increased Alveolar Macrophage Subpopulation in Old Mice That Displays Unique Inflammatory Characteristics and Is Permissive to Mycobacterium Tuberculosis Infection”. J Immunol 203: 2252-64. https://doi.org/10.4049/jimmunol.1900495.
The elderly population is more susceptible to pulmonary infections, including tuberculosis. In this article, we characterize the impact of aging on the phenotype of mouse alveolar macrophages (AMs) and their response to Mycobacterium tuberculosis. Uninfected AMs were isolated from bronchoalveolar lavage of young (3 mo) and old (18 mo) C57BL/6 mice. AMs from old mice expressed higher mRNA levels of CCL2, IFN-beta, IL-10, IL-12p40, TNF-alpha, and MIF than young mice, and old mice contained higher levels of CCL2, IL-1beta, IFN-beta, and MIF in their alveolar lining fluid. We identified two distinct AM subpopulations, a major CD11c(+) CD11b(-) population and a minor CD11c(+) CD11b(+) population; the latter was significantly increased in old mice (4-fold). Expression of CD206, TLR2, CD16/CD32, MHC class II, and CD86 was higher in CD11c(+) CD11b(+) AMs, and these cells expressed monocytic markers Ly6C, CX3CR1, and CD115, suggesting monocytic origin. Sorted CD11c(+) CD11b(+) AMs from old mice expressed higher mRNA levels of CCL2, IL-1beta, and IL-6, whereas CD11c(+) CD11b(-) AMs expressed higher mRNA levels of immune- regulatory cytokines IFN-beta and IL-10. CD11c(+) CD11b(+) AMs phagocytosed significantly more M. tuberculosis, which expressed higher RNA levels of genes required for M. tuberculosis survival. Our studies identify two distinct AM populations in old mice: a resident population and an increased CD11c(+) CD11b(+) AM subpopulation expressing monocytic markers, a unique inflammatory signature, and enhanced M. tuberculosis phagocytosis and survival when compared with resident CD11c(+) CD11b(-) AMs, which are more immune regulatory in nature.
Headley, C. A., A. Gerberick, S. Mehta, Q. Wu, L. Yu, P. Fadda, M. Khan, L. P. Ganesan, J. Turner, and M. V. S. Rajaram. 2019. “Nontuberculous Mycobacterium M. Avium Infection Predisposes Aged Mice to Cardiac Abnormalities and Inflammation”. Aging Cell 18: e12926. https://doi.org/10.1111/acel.12926.
Biological aging dynamically alters normal immune and cardiac function, favoring the production of pro-inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) and increased instances of cardiac distress. Cardiac failure is the primary reason for hospitalization of the elderly (65+ years). The elderly are also increasingly susceptible to developing chronic bacterial infections due to aging associated immune abnormalities. Since bacterial infections compound the rates of cardiac failure in the elderly, and this phenomenon is not entirely understood, the interplay between the immune system and cardiovascular function in the elderly is of great interest. Using Mycobacterium avium, an opportunistic pathogen, we investigated the effect of mycobacteria on cardiac function in aged mice. Young (2-3 months) and old (18-20 months) C57BL/6 mice were intranasally infected with M. avium strain 104, and we compared the bacterial burden, immune status, cardiac electrical activity, pathology, and function of infected mice against uninfected age-matched controls. Herein, we show that biological aging may predispose old mice infected with M. avium to mycobacterial dissemination into the heart tissue and this leads to cardiac dysfunction. M. avium infected old mice had significant dysrhythmia, cardiac hypertrophy, increased recruitment of CD45(+) leukocytes, cardiac fibrosis, and increased expression of inflammatory genes in isolated heart tissue. This is the first study to report the effect of mycobacteria on cardiac function in an aged model. Our findings are critical to understanding how nontuberculous mycobacterium (NTM) and other mycobacterial infections contribute to cardiac dysfunction in the elderly population.
Headley, C., J. Turner, and M. V. Rajaram. 2019. “Aging Heart and Infection”. Aging (Albany NY) 11: 4781-82. https://doi.org/10.18632/aging.102128.

2018

Guirado, Evelyn, Murugesan Vs Rajaram, Ajay Chawla, Joanna Daigle, Krista Md La Perle, Eusondia Arnett, Joanne Turner, and Larry S Schlesinger. (2018) 2018. “Deletion of PPARγ in Lung Macrophages Provides an Immunoprotective Response Against M. Tuberculosis Infection in Mice.”. Tuberculosis (Edinburgh, Scotland) 111: 170-77. https://doi.org/10.1016/j.tube.2018.06.012.
Publisher's Version

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear transcription factor belonging to the superfamily of ligand-activated nuclear receptors. It is activated by diverse endogenous lipid metabolites as well as by exogenous ligands such as the thiazolidinediones. It regulates cellular metabolism, proliferation, differentiation, and inflammation, the latter in part through trans-repression of pro-inflammatory cytokines. PPARγ is highly expressed in alternatively activated alveolar macrophages (AMs), a primary host cell for airborne Mycobacterium tuberculosis (M.tb). Our previous in vitro study identified the importance of PPARγ activation through the mannose receptor (CD206) on human macrophages in enabling M. tb growth. The aim of the current study was to investigate the role of PPARγ in vivo during M. tb infection using a macrophage-specific PPARγ knock out mouse model with special emphasis on the lung environment. Our data show that the absence of PPARγ in lung macrophages reduces the growth of virulent M. tb, enhances pro-inflammatory cytokines and reduces granulomatous infiltration. These findings demonstrate that PPARγ activation, which down-regulates macrophage pro-inflammatory responses, impacts the lung's response to M. tb infection, thereby supporting PPARγ's role in tuberculosis (TB) pathogenesis.

Turner, Joanne, and Jordi B Torrelles. (2018) 2018. “Mannose-Capped Lipoarabinomannan in Mycobacterium Tuberculosis Pathogenesis.”. Pathogens and Disease 76 (4). https://doi.org/10.1093/femspd/fty026.
Publisher's Version

Mannose-capped lipoarabinomannan (ManLAM), present in all members of the Mycobacterium tuberculosis complex and in other pathogenic Mycobacterium spp, is a high molecular mass amphipathic lipoglycan with a defined critical role in mycobacterial survival during infection. In particular, ManLAM is well-characterized for its importance in providing M. tuberculosis a safe portal of entry to phagocytes, regulating the intracellular trafficking network, as well as immune responses of infected host cells. These ManLAM immunological characteristics are thought to be linked to the subtle but unique and well-defined structural characteristics of this molecule, including but not limited to the degree of acylation, the length of the D-mannan and D-arabinan cores, the length of the mannose caps, as well as the presence of other acidic constituents such as succinates, lactates and/or malates, and also the presence of 5-methylthioxylosyl. The impact of all these structural features on ManLAM spatial conformation and biological functions during M. tuberculosis infection is still uncertain. In this review, we dissect the relationship between ManLAM structure and biological function addressing how this relationship determines M. tuberculosis interactions with host cells, and how it aids this exceptional pathogen during the course of infection.

Ault, R., V. Dwivedi, E. Koivisto, J. Nagy, K. Miller, K. Nagendran, I. Chalana, X. Pan, S. H. Wang, and J. Turner. 2018. “Altered Monocyte Phenotypes But Not Impaired Peripheral T Cell Immunity May Explain Susceptibility of the Elderly to Develop Tuberculosis”. Exp Gerontol 111: 35-44. https://doi.org/10.1016/j.exger.2018.06.029.
Tuberculosis (TB) is the leading killer due to a single infectious disease worldwide. With the aging of the global population, the case rate and deaths due to TB are highest in the elderly population. While general immunosenescence associated with old age is thought to contribute to the susceptibility of the elderly to develop active TB disease, very few studies of immune function in elderly individuals with Mycobacterium tuberculosis (M.tb) infection or disease have been performed. In particular, impaired adaptive T cell immunity to M.tb is one proposed mechanism for the elderly's increased susceptibility primarily on the basis of the decreased delayed type hypersensitivity response to tuberculin-purified protein derivative in the skin of elderly individuals. To investigate immunological reasons why the elderly are susceptible to develop active TB disease, we performed a cross-sectional observational study over a five year period (2012-2016) enrolling participants from 2 age groups (adults: 25-44years; elderly: 65 and older) and 3 M.tb infection statuses (active TB, latent TB infection, and healthy controls without history of M.tb infection). We hypothesized that impaired peripheral T cell immunity plays a role in the biological susceptibility of the elderly to TB. Contrary to our hypothesis, we observed no evidence of impaired M.tb specific T cell frequency or altered production of cytokines implicated in M.tb control (IFN-gamma, IL-10) in peripheral blood in the elderly. Instead, we observed alterations in monocyte proportion and phenotype with age and M.tb infection that suggest their potential role in the susceptibility of the elderly to develop active TB. Our results suggest a potential link between the known widespread low-grade systemic inflammation of old age, termed "inflammaging," with the elderly's specific susceptibility to developing active TB. Moreover, our results highlight the need for further research into the biological reasons why the elderly are more susceptible to disease and death from TB, so that public health systems can be better equipped to face the present and future problem of TB in an aging global population.
Piergallini, T. J., and J. Turner. 2018. “Tuberculosis in the Elderly: Why Inflammation Matters”. Exp Gerontol 105: 32-39. https://doi.org/10.1016/j.exger.2017.12.021.
Growing old is associated with an increase in the basal inflammatory state of an individual and susceptibility to many diseases, including infectious diseases. Evidence is growing to support the concept that inflammation and disease susceptibility in the elderly is linked. Our studies focus on the infectious disease tuberculosis (TB), which is caused by Mycobacterium tuberculosis (M.tb), a pathogen that infects approximately one fourth of the world's population. Aging is a major risk factor for developing TB, and inflammation has been strongly implicated. In this review we will discuss the relationship between inflammation in the lung and susceptibility to develop and succumb to TB in old age. Further understanding of the relationship between inflammation, age, and M.tb will lead to informed decisions about TB prevention and treatment strategies that are uniquely designed for the elderly.
Moliva, J. I., A. P. Hossfeld, C. H. Canan, V. Dwivedi, M. D. Wewers, G. Beamer, J. Turner, and J. B. Torrelles. 2018. “Exposure to Human Alveolar Lining Fluid Enhances Mycobacterium Bovis BCG Vaccine Efficacy Against Mycobacterium Tuberculosis Infection in a CD8(+) T-Cell-Dependent Manner”. Mucosal Immunol 11: 968-78. https://doi.org/10.1038/mi.2017.80.
Current tuberculosis (TB) treatments include chemotherapy and preventative vaccination with Mycobacterium bovis Bacillus Calmette- Guerin (BCG). In humans, however, BCG vaccination fails to fully protect against pulmonary TB. Few studies have considered the impact of the human lung mucosa (alveolar lining fluid (ALF)), which modifies the Mycobacterium tuberculosis (M.tb) cell wall, revealing alternate antigenic epitopes on the bacterium surface that alter its pathogenicity. We hypothesized that ALF-induced modification of BCG would induce better protection against aerosol infection with M.tb. Here we vaccinated mice with ALF-exposed BCG, mimicking the mycobacterial cell surface properties that would be present in the lung during M.tb infection. ALF-exposed BCG- vaccinated mice were more effective at reducing M.tb bacterial burden in the lung and spleen, and had reduced lung inflammation at late stages of M.tb infection. Improved BCG efficacy was associated with increased numbers of memory CD8(+) T cells, and CD8(+) T cells with the potential to produce interferon-gamma in the lung in response to M.tb challenge. Depletion studies confirmed an essential role for CD8(+) T cells in controlling M.tb bacterial burden. We conclude that ALF modifications to the M.tb cell wall in vivo are relevant in the context of vaccine design.