Pulmonary infection is a leading cause of hospitalization in world. Lung damage due to infection and host mediated pathology can have life threatening consequences. Factors that limit lung injury ...and/or promote epithelial barrier function and repair are highly desirable as immunomodulatory therapeutics. Over the last decade, interleukin-22 has been shown to have pulmonary epithelial protective functions at the mucosal immune interface with bacterial and viral pathogens. This article summarizes recent findings in this area and provides perspective regarding the role of IL-22 in mucosal host defense.
Seasonal influenza virus infection presents a major strain on the health care system. Influenza virus infection has pandemic potential, which was repeatedly observed during the last century. Severe ...disease may occur in the young, in the elderly, in those with preexisting lung disease, and in previously healthy individuals. A common cause of severe influenza pathogenesis is superinfection with bacterial pathogens, namely, Staphylococcus aureus and Streptococcus pneumoniae. A great deal of recent research has focused on the immune pathways involved in influenza-induced susceptibility to secondary bacterial pneumonia. Both innate and adaptive antibacterial host defenses are impaired in the context of preceding influenza virus infection. The goal of this minireview is to highlight these findings and synthesize these data into a shared central theme of pathogenesis.
Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Despite broad literature including basic and translational scientific studies, many gaps in our ...understanding of host-pathogen interactions remain. In this review, pathogen virulence factors that drive lung infection and injury are discussed in relation to their associated host immune pathways. CAP epidemiology is considered, with a focus on
and
as primary pathogens. Bacterial factors involved in nasal colonization and subsequent virulence are illuminated. A particular emphasis is placed on bacterial pore-forming toxins, host cell death, and inflammasome activation. Identified host-pathogen interactions are then examined by linking pathogen factors to aberrant host response pathways in the context of acute lung injury in both primary and secondary infection. While much is known regarding bacterial virulence and host immune responses, CAP management is still limited to mostly supportive care. It is likely that improvements in therapy will be derived from combinatorial targeting of both pathogen virulence factors and host immunomodulation.
TH17 cells in asthma and COPD Alcorn, John F; Crowe, Christopher R; Kolls, Jay K
Annual review of physiology,
2010, Letnik:
72
Journal Article
Recenzirano
Asthma and chronic obstructive pulmonary disease (COPD) represent two classes of chronic obstructive lung disorders that may share some similar immunologic mechanisms of disease. Asthma is a complex ...human disease characterized by airway hyperresponsiveness (AHR) and inflammation, whereas COPD is marked by progressive emphysematic changes in the lung. Recently it has been shown that advanced COPD is characterized by lymphoid follicles, drawing attention to immunological mechanisms in COPD. Despite numerous studies in mice to elucidate the immunologic mechanisms of asthma, sufficient current treatment options are limited. Clinically, many asthma patients fail to satisfactorily respond to standard steroid therapy, and this type of steroid-resistant, severe asthma has been linked to the presence of neutrophilic inflammation in the lung. The role of neutrophils, macrophages, and their secreted proteases in COPD needs to be better defined. Recently, the T lymphocyte subset T(H)17 was shown to play a role in regulating neutrophilic and macrophage inflammation in the lung, suggesting a potential role for T(H)17 cells in severe, steroid-insensitive asthma and COPD.
The interleukin-17 (IL-17) family of cytokines phylogenetically predates the evolution of T cells in jawed vertebrates, suggesting that the ontogeny of the Th17 cell lineage must have arisen to ...confer an evolutionary advantage to the host over innate sources of IL-17. Utilizing a model of mucosal immunization with the encapsulated bacteria
Klebsiella pneumoniae, we found that B cells, which largely recognized polysaccharide capsular antigens, afforded protection to only the vaccine strain. In contrast, memory Th17 cells proliferated in response to conserved outer membrane proteins and conferred protection against several serotypes of
K. pneumoniae, including the recently described multidrug resistant New Dehli metallolactamase strain. Notably, this heterologous, clade-specific protection was antibody independent, demonstrating the Th17 cell lineage confers a host advantage by providing heterologous mucosal immunity independent of serotype-specific antibody.
► Th17 cells generated by vaccination confer cross-serotype protection ► Memory Th17 cells mediate direct protection in an antigen-specific manner ► Th17 cells protect against multidrug resistant
Klebsiella challenge
Interferon (IFN) represents a well-known component of antiviral immunity that has been studied extensively for its mechanisms of action and therapeutic potential when antiviral treatment options are ...limited. Specifically in the respiratory tract, IFNs are induced directly on viral recognition to limit the spread and transmission of the virus. Recent focus has been on the IFNλ family, which has become an exciting focus in recent years for its potent antiviral and anti-inflammatory activities against viruses infecting barrier sites, including the respiratory tract. However, insights into the interplay between IFNλs and other pulmonary infections are more limited and suggest a more complex role, potentially detrimental, than what was seen during viral infections. Here, we review the role of IFNλs in pulmonary infections, including viral, bacterial, fungal, and multi-pathogen super-infections, and how this may impact future work in the field.
Influenza kills 30,000 to 40,000 people each year in the United States and causes 10 times as many hospitalizations. A common complication of influenza is bacterial superinfection, which exacerbates ...morbidity and mortality from the viral illness. Recently, methicillin-resistant
(MRSA) has emerged as the dominant pathogen found in bacterial superinfection, with
a close second. However, clinicians have few tools to treat bacterial superinfection. Current therapy for influenza/bacterial superinfection consists of treating the underlying influenza infection and adding various antibiotics, which are increasingly rendered ineffective by rising bacterial multidrug resistance. Several groups have recently proposed the use of the antiviral cytokine interferon lambda (IFN-λ) as a therapeutic for influenza, as administration of pegylated IFN-λ improves lung function and survival during influenza by reducing the overabundance of neutrophils in the lung. However, our data suggest that therapeutic IFN-λ impairs bacterial clearance during influenza superinfection. Specifically, mice treated with an adenoviral vector to overexpress IFN-λ during influenza infection exhibited increased bacterial burdens upon superinfection with either MRSA or
Surprisingly, adhesion molecule expression, antimicrobial peptide production, and reactive oxygen species activity were not altered by IFN-λ treatment. However, neutrophil uptake of MRSA and
was significantly reduced upon IFN-λ treatment during influenza superinfection
Together, these data support the theory that IFN-λ decreases neutrophil motility and function in the influenza-infected lung, which increases the bacterial burden during superinfection. Thus, we believe that caution should be exercised in the possible future use of IFN-λ as therapy for influenza.
Angiotensin-converting enzyme 2 (ACE2) is a potent negative regulator capable of restraining overactivation of the renin-angiotensin system, which contributes to exuberant inflammation after ...bacterial infection. However, the mechanism through which ACE2 modulates this inflammatory response is not well understood. Accumulating evidence indicates that infectious insults perturb ACE2 activity, allowing for uncontrolled inflammation. In the current study, we demonstrate that pulmonary ACE2 levels are dynamically varied during bacterial lung infection, and the fluctuation is critical in determining the severity of bacterial pneumonia. Specifically, we found that a pre-existing and persistent deficiency of active ACE2 led to excessive neutrophil accumulation in mouse lungs subjected to bacterial infection, resulting in a hyperinflammatory response and lung damage. In contrast, pre-existing and persistent increased ACE2 activity reduces neutrophil infiltration and compromises host defense, leading to overwhelming bacterial infection. Further, we found that the interruption of pulmonary ACE2 restitution in the model of bacterial lung infection delays the recovery process from neutrophilic lung inflammation. We observed the beneficial effects of recombinant ACE2 when administered to bacterially infected mouse lungs following an initial inflammatory response. In seeking to elucidate the mechanisms involved, we discovered that ACE2 inhibits neutrophil infiltration and lung inflammation by limiting IL-17 signaling by reducing the activity of the STAT3 pathway. The results suggest that the alteration of active ACE2 is not only a consequence of bacterial lung infection but also a critical component of host defense through modulation of the innate immune response to bacterial lung infection by regulating neutrophil influx.
The absent in melanoma 2 (AIM2) inflammasome plays an important role in many viral and bacterial infections, but very little is known about its role in RNA virus infection, including influenza A ...virus (IAV). In this study, we have designed in vivo and in vitro studies to determine the role of AIM2 in infections with lethal doses of IAVs A/PR8/34 and A/California/07/09. In wild-type mice, IAV infection enhanced AIM2 expression, induced dsDNA release, and stimulated caspase-1 activation and release of cleaved IL-1β in the lung, which was significantly reduced in AIM2-deficient mice. Interestingly, AIM2 deficiency did not affect the transcription of caspase-1 and IL-1β. In addition, AIM2-deficient mice exhibited attenuated lung injury and significantly improved survival against IAV challenges, but did not alter viral burden in the lung. However, AIM2 deficiency did not seem to affect adaptive immune response against IAV infections. Furthermore, experiments with AIM2-specific small interfering RNA-treated and AIM2-deficient human and mouse lung alveolar macrophages and type II cells indicated a macrophage-specific function of AIM2 in regulation of IAV-stimulated proinflammatory response. Collectively, our results demonstrate that influenza infection activates the AIM2 inflammasome, which plays a critical role in IAV-induced lung injury and mortality. AIM2 might serve as a therapeutic target for combating influenza-associated morbidity and mortality without compromising the host antiviral responses.
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