The Upper and Lower Respiratory Tracts Differ in Their Requirement of IFN-γ and IL-4 in Controlling Respiratory Mycoplasma Infection and Disease

Abstract

The purpose of this study is to evaluate the significance of IFN-γ and IL-4 production in controlling mycoplasma infection and the pathogenesis of disease in the upper and lower respiratory tract. By using IFN-γ knockout and IL-4 knockout BALB/c mice, we were able to study the contribution of these cytokines in the development of pathogenesis and/or protection in response to mycoplasma respiratory infection, in both the upper and lower respiratory tracts. The loss of either IFN-γ or IL-4 does not affect disease pathogenesis or mycoplasma organism numbers in the upper respiratory tract. However, in the absence of IL-4, the nasal passages developed a compensatory immune response, characterized by higher numbers of macrophages and CD8+ T cells, which may be masking detrimental effects due to IL-4 deficiency. This is in contrast to the lower respiratory tract, where the loss of IFN-γ, but not IL-4, leads to higher mycoplasma numbers and increased disease severity. The loss of IFN-γ impacted the innate immune system’s ability to effectively clear mycoplasma, as the number of organisms was higher by day 3 postinfection. This higher organism burden most likely impacted disease pathogenesis; however, the development of Th2 cell-mediated adaptive immune response most likely contributed to lesion severity at later time points during infection. Our studies demonstrate that the upper and lower respiratory tracts are separate and distinct in their cytokine requirements for generating immunity against mycoplasma infection.

The Complex Mechanism of Antibody-Mediated Clearance of Bordetella from the Lungs Requires TLR4

“…It is widely accepted that there are significant differences in the immune responses generated in the upper and lower respiratory tracts (36). This is reflected by the fact that the upper respiratory tract is more permissive of bacterial colonization than the lower respiratory tract (37).…”

RespiratoryFrancisella tularensisLive Vaccine Strain Infection Induces Th17 Cells and Prostaglandin E2, Which Inhibits Generation of Gamma Interferon-Positive T Cells

“…Airway cells were collected by bronchoalveolar lavage as previously described (48). Bronchoalveolar lavage fluid (BALF) was collected and frozen at Ϫ80°C for later analysis.…”

The Contrasting Roles of T Regulatory Cells in Bacterial Lung Diseases

“…Mice lacking IFN- (which preferentially mounted a Th2 cell response) developed more severe disease upon infection with Mycoplasma pulmonis at an early time point (Woolard et al, 2004). In contrast, mice lacking IL-4 (which preferentially mounted a Th1 cell response) did not demonstrate any exacerbation of disease (Woolard et al, 2004). Furthermore, immunization with mycoplasma antigen results in resistance to infection in IL-4-deficient mice, but not IFN- deficient mice (Bodhankar et al, 2010).…”

“…Since Th cell responses can be separated into Th1 or Th2 lineages, further studies were performed using IFN--deficient mice and IL-4-deficient mice. Mice lacking IFN- (which preferentially mounted a Th2 cell response) developed more severe disease upon infection with Mycoplasma pulmonis at an early time point (Woolard et al, 2004). In contrast, mice lacking IL-4 (which preferentially mounted a Th1 cell response) did not demonstrate any exacerbation of disease (Woolard et al, 2004).…”

“…While most cases of Mycoplasma infection are not life threatening, some do require hospitalization (more than 100,000 people per year). Mycoplasmas have also been suggested to have a role in the exacerbation of chronic asthma and certain autoimmune conditions (Atkinson et al, 2008;Dobbs et al, 2010;Woolard et al, 2004).…”