Article

Lung Infection—A Public Health Priority

Harvard School of Public Health, Boston, Massachusetts, USA.
PLoS Medicine (Impact Factor: 14). 03/2006; 3(2):e76. DOI: 10.1371/journal.pmed.0030076
Source: PubMed

ABSTRACT The pervasive burden of lung infections receives proportionately little attention from the biomedical and public health communities, argues Mizgerd.

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    • "Infectious pneumonias are a leading cause of worldwide morbidity and mortality, with a greater annual burden of disease than HIV, malaria, and tuberculosis (Mizgerd, 2006). The bacterium Yersinia pestis is an infamous example of an easily transmitted pathogen that causes respiratory infections. "
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    ABSTRACT: Pneumonic plague is a deadly respiratory disease caused by Yersinia pestis. The bacterial protease Pla contributes to disease progression and manipulation of host immunity, but the mechanisms by which this occurs are largely unknown. Here we show that Pla degrades the apoptotic signaling molecule Fas ligand (FasL) to prevent host cell apoptosis and inflammation. Wild-type Y. pestis, but not a Pla mutant (Δpla), degrades FasL, which results in decreased downstream caspase-3/7 activation and reduced apoptosis. Similarly, lungs of mice challenged with wild-type Y. pestis show reduced levels of FasL and activated caspase-3/7 compared to Δpla infection. Consistent with a role for FasL in regulating immune responses, Δpla infection results in aberrant proinflammatory cytokine levels. The loss of FasL or inhibition of caspase activity alters host inflammatory responses and enables enhanced Y. pestis outgrowth in the lungs. Thus, by degrading FasL, Y. pestis manipulates host cell death pathways to facilitate infection.
    Cell host & microbe 04/2014; 15(4):424-34. DOI:10.1016/j.chom.2014.03.005 · 12.19 Impact Factor
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    • "The World Health Organization (WHO) estimates that lower respiratory tract infections account for nearly 35% of all deaths from infectious diseases, causing an annual mortality of nearly 4 million adults and children. Thus, bacterial pneumonia is a significant cause of mortality worldwide 1. "
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    ABSTRACT: Objective: In the acute stage of infectious diseases such as pneumonia and sepsis, sequelae hypercytokinemia and cytokine storm are often observed simultaneously. During bacterial infections, activated polymorphonuclear leukocytes (PMNs) cause inflammation and organ dysfunction in severely ill patients. Gene expression of the triggering receptor on myeloid cells (TREM)-1 and G-coupled-protein receptor kinase (GRK)-2 in PMNs isolated from patients was analysed to identify genes correlated with the severity of pathophysiological conditions. Methods: mRNA levels of TREM1 and GRK2 in the PMNs from 26 patients (13 with pneumonia, 5 with severe sepsis, and 8 with septic shock) were analysed by using quantitative real-time PCR. The synthesised soluble form (s)TREM-1 was incubated with normal PMNs to investigate its biological functions in vitro. Results: Copies of TREM1 transcript were 0.7- to 2.1-fold higher in patients with pneumonia compared to those of normal subjects; the average fold-change was 1.1-fold. The mRNA levels of patients suffering from severe sepsis and septic shock were 0.34- and 0.33-fold lower compared to those of healthy subjects, respectively. TREM1 mRNA levels in 5 of 26 patients in convalescent stages recovered to normal levels. The mRNA levels of GRK2 in the PMNs of patients were also downregulated. The synthesised sTREM-1 upregulated the mRNA levels of TREM1 in normal PMNs. Conclusions: TREM1 mRNA levels were inversely correlated with the severity of pathophysiological conditions in acute bacterial infections. The gene expression levels of TREM1 in PMNs isolated from patients with bacterial infections may be used as a surrogate biomarker for determining the severity.
    International journal of medical sciences 01/2014; 11(2):215-21. DOI:10.7150/ijms.7231 · 1.55 Impact Factor
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    • "September 2013 | Volume 3 | Article 52 | 3 Abraham, 2003; Mizgerd, 2006, 2008; Balamayooran et al., 2010). Therefore, once the pathogen is cleared, the immediate next goal of the host is to mount an appropriate anti-inflammatory response to limit further neutrophil recruitment. "
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    ABSTRACT: Ligand-mediated activation of toll-like receptors (TLRs) not only induces inflammation but also immune suppression, which is an emerging area of investigation. Multiple negative feedback intracellular mechanisms have been described that are brought into play to prevent uncontrolled TLR activation. However, the identification of TLR-induced regulatory myeloid cells is a relatively recent development that has ramifications in pathogen-induced disease state as well as in cancer. Our efforts to understand how a high dose of lipopolysaccharide (LPS), a ligand of TLR4, suppresses allergic airway inflammation led to the identification of myeloid cells that are CD11b(+)Gri(int)(Ly6G(int))F4/80(+) and are phenotypically and morphologically similar to myeloid-derived suppressor cells (MDSCs) which are best studied in the context of cancer. MDSCs have been also detected during infection by various bacteria, parasites and viruses, which can engage different TLRs. These TLR-induced myeloid cells produce different types of mediators to influence immune response and inflammation that can be either beneficial or detrimental to the host. One beneficial function of TLR4/MyD88-triggered MDSCs in the lung is to efferocytose apoptotic neutrophils to help resolve inflammation elicited during bacterial pneumonia. A better understanding of the generation and function of these regulatory cells would be helpful to harness their potential or suppress their function for disease-specific immune regulation.
    Frontiers in Cellular and Infection Microbiology 09/2013; 3:52. DOI:10.3389/fcimb.2013.00052 · 2.62 Impact Factor
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