Elsevier

Clinical Immunology

Volume 124, Issue 3, September 2007, Pages 238-243
Clinical Immunology

Short Analytical Review
Role of Toll-like receptors in lung innate defense against invasive aspergillosis. Distinct impact in immunocompetent and immunocompromized hosts

https://doi.org/10.1016/j.clim.2007.05.004Get rights and content

Abstract

Toll-like receptors are key to pathogen recognition by a host and to the subsequent triggering of an innate immune response. Experimental and clinical evidence shows that defects in Toll-like receptors or in signaling pathways downstream from these receptors render hosts susceptible to various types of infection, including aspergillosis. Patients receiving an immunosuppressive regimen, including corticosteroid therapy or cytotoxic chemotherapy, are also susceptible to infections. Aspergillus fumigatus is an opportunistic pathogen that infects the lungs of immunosuppressed hosts. Here, we review the evidence that experimental inactivation of various Toll-like receptors and of their signaling pathways may worsen cases of invasive pulmonary aspergillosis. Moreover, the literature clearly indicates that the type of immunosuppression is very important, as it influences whether or not Toll-like receptors contribute to infection. The involvement of Toll-like receptors, based on the immunological status of the patient, should be considered if an immunosuppressive treatment must be administered.

Section snippets

Contribution of Toll-like receptors (TLRs) to the innate immune response of the host

In recent years, the TLR family has emerged as a major group of pathogen-recognition receptors that play a central role in the induction of immune responses. Humans express at least 10 TLRs involved in the recognition of various pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS), a major component of Gram-negative bacteria and detected by TLR4, as well as lipopeptides produced mainly by Gram-positive bacteria and detected by TLR2. Other interactions include those

The innate immune response to A. fumigatus

A. fumigatus is an airborne fungus. Its conidia are small enough to reach the alveoli easily during breathing. In immunocompromised patients, conidia germinate, and hyphae develop and invade the parenchyma. This leads to tissue destruction and respiratory failure characteristic of invasive pulmonary aspergillosis (IPA), a life-threatening disease with a death rate higher than 60% [5]. Mortality from IPA has increased several-fold during the last 20 year period, a finding that is explained by

Immunosuppression and TLRs

Whereas MyD88−/−, TLR2−/−, and/or TLR4−/− neutropenic mice do not survive A. fumigatus pulmonary infection, immunocompetent mice do [30], [31], [34]. Therefore, TLR2 and/or TLR4 are essential in the absence of PMN, but not in the healthy host. This suggests that TLRs expressed by PMN are not as important in vivo as other pathogen-recognition receptors expressed by PMN. One such critical pathogen-recognition receptor may be Dectin-1, a β-glucan receptor. It is expressed by PMN [35] and is

Clinical relevance and conclusion

Our understanding of how the immune system recognizes pathogens has greatly increased in recent years, due to the discovery of TLRs. They play a central role in the detection of PAMPs and in the initiation of effective innate and adaptive immune responses [1], [2], [3]. There is accumulating evidence, based on in vitro and in vivo studies, that supports a role for TLRs in A. fumigatus sensing. Several clinical reports confirm that TLRs contribute to the pathophysiology of infectious diseases

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