53 research outputs found
Interferons in immunity to chlamydia pneumoniae
The cytokine IFN-gamma is the architect behind an amazing immunological
program of host resistance to intracellular bacterial and protozoan
infections. IFN-gamma activates macrophages, making them into
inhospitable habitats for parasites attempting to grow inside them. The
family of obligate intracellular Gram-negative bacteria Chlamydia is an
example of such pathogens. The overall aim of this thesis was to unravel
resistance to infection with the human respiratory pathogen C. pneumoniae.
Specific focus was placed on innate immune responses to C. pneumoniae and
the regulation and role of IFN-gamma in the outcome of infection. An
experimental mouse model of lung infection and a macrophage model of in
vitro infection were used for this purpose.
A protective role for infection-induced IFN-gamma in restricting C.
pneumoniae growth in vivo was observed, though IFN-gamma was not required
for resolution of infection. IL-12 and/or IL-23 was a necessary but not
an absolute requirement for expression of IFN-gamma. IFN-gamma-dependent
protection was in part mediated by iNOS expression. TNF-alpha, known to
be synergistic with IFN-gamma, was not required for restricting
Chlamydial growth. Innate immune cells in the lung constituted an
important source of IFN-gamma and were essential for restricting C.
pneumoniae growth and for containment of bacteria in the lungs. However,
NK cells were not implicated in such protective IFN-gamma release. On the
other hand, lung macrophages isolated from C.pneumoniae-infected mice
expressed IFN-gamma. Moreover, bone marrow-derived macrophages (BMMphi)
conferred upon transfer to RAG-1-/-/IFN-gamma-/-mice, enhanced resistance
to C. pneumoniae infection via their ability to release IFN-gamma. Innate
IFN-gamma was however not required for protection conferred by CD4+ or
CD8+ T cells. Innate and T cell-derived IFN-gamma are also non-redundant
(complementary) in protesting mice against C. pneumoniae.
C. pneumoniae-infected BMMphi also expressed IFN-gamma in vitro. Such
IFN-gamma release was IL-12independent but required instead
IFN-alpha/beta and restricted Chlamydial growth. IFN-alpha/beta, and not
IFNgamma, was required for iNOS-mediated protection in BMMphi. The
molecular details of BMMphi-derived IFNgamma expression revealed a
TLR4-MyD88-dependent pathway of IFN-alpha and IFN-gamma induction. Also
surprising was the presente of a TLR4- and MyD88-independent,
infection-induced NF-kappaB activation and proinflammatory cytokine
expression. Phosphorylation of STAT1 during infection was
IFN-alpha/beta-dependent, and necessary for increased IFN-gamma
expression and for restricting Chlamydial growth. Expression of IFN-gamma
and restriction of C. pneumoniae growth also required NF-kappaB
activation, but such activation was independent of IFN-alpha/beta,
revealing a dual pathway of C.pneumoniae-induced IFN-gamma expression in
BMMphi: a TLR4-MyD88-IFNalpha/beta-STAT1 -dependent pathway, and a
TLR4-independent pathway leading to NF-kappaB activation.
IFN-alpha/beta was also protective in vivo by cooperating with IFN-gamma
for activation of STAT1, which was required for restricting Chlamydial
growth. Different from the in vitro situation, IFN-gamma was sufficient
on its own for this effect and did not require IFN-alpha/beta for its
expression.
In summary, IFN-gamma is important for restricting C. pneumoniae growth.
Innate IFN-gamma is protective both in lungs and in BMMphi.
IFN-alpha/beta are pivotal in regulating protective responses in BMMphi,
including IFNgamma release, but are dispensable for IFN-gamma expression
and protection in vivo. This discrepancy may be a qualitative feature in
C. pneumoniae pattern recognition by different cell types; lung cells
convey the generation of protective, IL-12-driven responses, while
IFN-alpha/beta-driven protection in BMMphi is essential
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Mannose-Binding Lectin Regulates Host Resistance and Pathology during Experimental Infection with Trypanosoma cruzi
Mannose-binding lectin (MBL) is a humoral pattern-recognition molecule important for host defense. Although recent genetic studies suggest an involvement of MBL/MASP2-associated pathways in Chagas’ disease, it is currently unknown whether MBL plays a role in host resistance to the intracellular protozoan Trypanosoma cruzi, the causative agent of Chagas’ disease. In this study we employed MBL−/− mice to assess the role of MBL in resistance to experimental infection with T. cruzi. T. cruzi infection enhanced tissue expression of MBL both at the mRNA and protein level. Similarly, symptomatic acute Chagas’ disease patients displayed increased serum concentrations of MBL compared to patients with indeterminate, asymptomatic forms of the disease. Furthermore, increased parasite loads in the blood and/or tissue were observed in MBL−/− mice compared to WT controls. This was associated with reduced systemic levels of IL-12/23p40 in MBL−/− mice. Importantly, MBL−/− mice infected with a cardiotropic strain of T. cruzi displayed increased myocarditis and cardiac fibrosis compared to WT controls. The latter was accompanied by elevated hydroxyproline content and mRNA levels of collagen-1 and -6 in the heart. These observations point to a previously unappreciated role for MBL in regulating host resistance and cardiac inflammation during infection with a major human pathogen
Detection and isolation of airborne SARS-CoV-2 in a hospital setting
Transmission mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are incompletely understood. In particular, aerosol transmission remains unclear, with viral detection in air and demonstration of its infection potential being actively investigated. To this end, we employed a novel electrostatic collector to sample air from rooms occupied by COVID-19 patients in a major Swedish hospital. Electrostatic air sampling in conjunction with extraction-free, reverse-transcriptase polymerase chain reaction (hid-RT-PCR) enabled detection of SARS-CoV-2 in air from patient rooms (9/22; 41%) and adjoining anterooms (10/22; 45%). Detection with hid-RT-PCR was concomitant with viral RNA presence on the surface of exhaust ventilation channels in patients and anterooms more than 2 m from the COVID-19 patient. Importantly, it was possible to detect active SARS-CoV-2 particles from room air, with a total of 496 plaque-forming units (PFUs) being isolated, establishing the presence of infectious, airborne SARS-CoV-2 in rooms occupied by COVID-19 patients. Our results support circulation of SARS-CoV-2 via aerosols and urge the revision of existing infection control frameworks to include airborne transmission
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