Airway infection, such as atypical bacterium Mycoplasma pneumoniae (Mp), contributes to asthma pathobiology. One key unanswered question is: What are the lung immunologic and molecular mechanisms by which asthmatics are susceptible to bacterial infections? Specifically, does an established allergic airway milieu in asthmatics enhance host susceptibility to Mp infection? Our previous studies in mouse models and human primary airway epithelial cell cultures have demonstrated that: 1) Mp activates Toll-like receptor 2 (TLR2) signaling pathway in mouse lungs including airway epithelial cells and dendritic cells (DCs), and human primary bronchial epithelial cells;2) TLR2 activation is critical for host defense against Mp infection through induction of Th1 response and antimicrobial substances;3) Allergic inflammation and/or Th2 cytokines reduce TLR2 activation, leading to an impaired lung Mp clearance (or a persistent low level of Mp);4) TLR2 activation using Pam3CSK4 (a TLR2 ligand) or neutralizing IL-4 and IL-13 in allergic mice restore the impaired Mp clearance;and 5) In an established allergic milieu, Mp infection, particularly at a low dose, increases Th2 differentiation. Our preliminary studies led us to hypothesize that an established allergic airway milieu down-regulates innate immunity (i.e., TLR2 activation), predisposes the host to a persistent low level of Mp infection, and consequently leads to an increased allergic airway response. To test this central hypothesis, we have proposed three specific aims.
Aim 1 is to test the hypothesis that an established allergic airway milieu reduces TLR2 activation in Mp-infected mice, leading to a persistent low level of lung Mp. TLR2 activation (use of TLR2 ligand Pam3CSK4 or adoptive DC transfer) prior to the establishment of allergic inflammation will restore the impaired Mp clearance in allergic lungs by promoting the Th1 response.
Aim 2 is to test the hypothesis that upon Mp infection, Th2 cytokines (IL-4, IL-13) inhibit TLR2 activation of airway epithelial cells (less TLR2 and antimicrobial substances) and lung DCs (less TLR2 and Th1-driving cytokine [e.g., IL-12] production). IL-4 and IL-13 inhibit Mp-induced TLR2 activation through suppressing NF-?B activity via signal transducer and activator of transcription 6 (STAT6) signaling pathway.
Aim 3 is to test the hypothesis that in contrast to higher doses, lower doses of Mp in an allergic milieu enhance allergic responses. Lower doses of Mp fail to induce TLR2 activation in Th2 cytokine-exposed DCs, leading to a DC phenotype (e.g., increased Jagged1 expression) in favor of Th2 differentiation of naive CD4+ T cells. Our proposed studies will reveal novel molecular mechanisms involved in an increased susceptibility of asthmatics to bacterial infections, which will provide the basic information in the design of therapeutic strategies to attenuate airway infectious and allergic processes in asthma. Project Narrative: Our research findings will significantly advance our knowledge with regard to the mechanisms of an increased susceptibility of asthmatics to bacterial infections, thus helping the design of novel therapeutic strategies in attenuating airway infectious and allergic processes in asthma and perhaps other chronic pulmonary diseases.
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