Lungs Of Infected Individuals Research Articles

Analysis of histopathology and changes of major cytokines in the lesions caused by Mycoplasma ovipneumoniae infection

BackgroundMycoplasma ovipneumoniae (M. ovipneumoniae) is one of the main pathogens of sheep pneumonia, causing a series of clinical symptoms, such as depression, anorexia, hyperthermia, cough, dyspnea, and tract secretions. In recent years, the prevalence of M. ovipneumoniae pneumonia has become increasingly serious in sheep farms in Ningxia, China, leading to the death of sheep, and causing significant economic losses. In this study, the pathological organs infected by M. ovipneumoniae were collected to observe histopathological change, to determine the tissue localization of M. ovipneumoniae, and to analyze the cytokine changes, which lays a basis for the diagnosis and pathogenesis of M. ovipneumoniae disease.ResultsIn this study, M. ovipneumoniae was detected in 97 of 105 samples collected from 13 large-scale sheep farms for nucleic acid by PCR. One representative isolate per farm was isolated from 13 farms. The lesions caused by M. ovipneumoniae were mainly in the trachea, bronchus, and lung, including necrosis of tracheal mucosal epithelial cells, disintegration of some epithelial cells, edema of mucosal lamina propria, with inflammatory cell infiltration, cytoplasmic vacuolization of epithelial cells of bronchial mucosa, massive infiltration of inflammatory cells in the alveolar space of lung, necrosis and hyperplasia of alveolar epithelial cells. Immunohistochemical analysis showed that the proportion of M. ovipneumoniae positive area in the lung was the largest, followed by that in the bronchus and trachea. Compared to healthy animals, diseased animals exhibited up-regulated gene expression levels of IL-1β, IL-6, and NF-κB in the trachea, bronchus, and lungs. In contrast, the expression of IL-10, IL-12, and IFN-γ was primarily limited to the trachea and bronchus. The expression of IL-1β showed differential patterns across different lung regions, with variations observed among lung lobes. Additionally, other cytokines consistently showed significant up-regulation specifically in the bronchus.ConclusionsM. ovipneumoniae is primarily found in the lungs of infected individuals. NF-κB, an essential transcription factor, is involved in the regulation of IL-1β transcription. IL-12 may enhance the cytotoxic function of natural killer cells during M. ovipneumoniae infection. Those findings demonstrate the distinct expression profiles of cytokines in various anatomical sites throughout disease progression, suggesting the potential role of bronchial tissue as a major site of immune response.

NOTCH signaling in COVID-19: a central hub controlling genes, proteins, and cells that mediate SARS-CoV-2 entry, the inflammatory response, and lung regeneration.

In the lungs of infected individuals, the downstream molecular signaling pathways induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are incompletely understood. Here, we describe and examine predictions of a model in which NOTCH may represent a central signaling axis in lung infection in Coronavirus Disease 2019 (COVID-19). A pathway involving NOTCH signaling, furin, ADAM17, and ACE2 may be capable of increasing SARS-CoV-2 viral entry and infection. NOTCH signaling can also upregulate IL-6 and pro-inflammatory mediators induced to hyperactivation in COVID-19. Furthermore, if NOTCH signaling fails to turn down properly and stays elevated, airway regeneration during lung healing can be inhibited—a process that may be at play in COVID-19. With specific NOTCH inhibitor drugs in development and clinical trials for other diseases being conducted, the roles of NOTCH in all of these processes central to both infection and healing merit contemplation if such drugs might be applied to COVID-19 patients.

Immune responses and pathogenesis of SARS-CoV-2 during an outbreak in Iran: Comparison with SARS and MERS.

SummaryThe beginning of 2020 has seen the emergence of COVID‐19, an outbreak caused by a novel coronavirus, SARS‐CoV‐2, an important pathogen for humans. There is an urgent need to better understand this new virus and to develop ways to control its spread. In Iran, the first case of the COVID‐19 was reported after spread from China and other countries. Fever, cough, and fatigue were the most common symptoms of this virus. In worldwide, the incubation period of COVID‐19 was 3 to 7 days and approximately 80% of infections are mild or asymptomatic, 15% are severe, requiring oxygen, and 5% are critical infections, requiring ventilation. To mount an antiviral response, the innate immune system recognizes molecular structures that are produced by the invasion of the virus. COVID‐19 infection induces IgG antibodies against N protein that can be detected by serum as early as day 4 after the onset of disease and with most patients seroconverting by day 14. Laboratory evidence of clinical patients showed that a specific T‐cell response against SARS‐CoV‐2 is important for the recognition and killing of infected cells, particularly in the lungs of infected individuals. At present, there is no specific antiviral therapy for COVID‐19 and the main treatments are supportive. In this review, we investigated the innate and acquired immune responses in patients who recovered from COVID‐19, which could inform the design of prophylactic vaccines and immunotherapy for the future.

Are Cancer Patients at Higher Risk of Death With COVID-19?

Are Cancer Patients at Higher Risk of Death With COVID-19?

Mycobacterial trehalose 6,6′-dimycolate induced vascular occlusion is accompanied by subendothelial inflammation

Mycobacterium tuberculosis (MTB) is a pathogen that infects and kills millions yearly. The mycobacterium's cell wall glycolipid trehalose 6,6′-dimycolate (TDM) has been used historically to model MTB induced inflammation and granuloma formation. Alterations to the model can significantly influence the induced pathology. One such method incorporates intraperitoneal pre-exposure, after which the intravenous injection of TDM generates pathological damage effectively mimicking the hypercoagulation, thrombus formation, and tissue remodeling apparent in lungs of infected individuals. The purpose of these experiments is to examine the histological inflammation involved in the TDM mouse model that induces development of the hemorrhagic response. TDM induced lungs of C57BL/6 mice to undergo granulomatous inflammation. Further histological examination of the peak response demonstrated tissue remodeling consistent with hypercoagulation. The observed vascular occlusion indicates that obstruction likely occurs due to subendothelial localized activity leading to restriction of blood vessel lumens. Trichrome staining revealed that associated damage in the hypercoagulation model is consistent with intra endothelial cell accumulation of innate cells, bordered by collagen deposition in the underlying parenchyma. Overall, the hypercoagulation model represents a comparative pathological instrument for understanding mechanisms underlying development of hemorrhage and vascular occlusion seen during MTB infection.

MicroRNA expression signatures in lungs of mice infected with Mycobacterium tuberculosis

Tuberculosis (TB) is a major public health concern worldwide; however the factors that account for resistance or susceptibility to disease are not completely understood. Although some studies suggest that the differential expression of miRNAs in peripheral blood of TB patients could be useful as biomarkers of active disease, their involvement during the inflammatory process in lungs of infected individuals is unknown. Here, we evaluated the global expression of miRNAs in the lungs of mice experimentally infected with Mycobacterium tuberculosis on 30 and 60 days post-infection. We observed that several miRNAs were differentially expressed compared to uninfected mice. Furthermore, we verified that the expression of miR-135b, miR-21, miR-155, miR-146a, and miR-146b was significantly altered in distinct leukocyte subsets isolated from lungs of infected mice, while genes potentially targeted by those miRNAs were associated with a diversity of immune related molecular pathways. Importantly, we validated the inhibition of Pellino 1 expression by miR-135b in vitro. Overall, this study contributes to the understanding of the dynamics of miRNA expression in lungs during experimental TB and adds further perspectives into the role of miRNAs on the regulation of immune processes such as leukocyte activation.

Isoniazid as a substrate and inhibitor of myeloperoxidase: Identification of amine adducts and the influence of superoxide dismutase on their formation

Neutrophils ingest Mycobacteria tuberculosis (Mtb) in the lungs of infected individuals. During phagocytosis they use myeloperoxidase (MPO) to catalyze production of hypochlorous acid (HOCl), their most potent antimicrobial agent. Isoniazid (INH), the foremost antibiotic in the treatment of tuberculosis, is oxidized by MPO. It rapidly reduced compound I of MPO [k=(1.22±0.05)×106M−1s−1] but reacted less favorably with compound II [(9.8±0.6)×102M−1s−1]. Oxidation of INH by MPO and hydrogen peroxide was unaffected by chloride, the physiological substrate for compound I, and the enzyme was partially converted to compound III. This indicates that INH is oxidized outside the classical peroxidation cycle. In combination with superoxide dismutase (SOD), MPO oxidized INH without exogenous hydrogen peroxide. SOD must favor reduction of oxygen by the INH radical to give superoxide and ultimately hydrogen peroxide. In both oxidation systems, an adduct with methionine was formed and it was a major product with MPO and SOD. We show that it is a conjugate of an acyldiimide with amines. INH substantially inhibited HOCl production by MPO and neutrophils below pharmacological concentrations. The reversible inhibition is explained by diversion of MPO to its ferrous and compound III forms during oxidation of INH. MPO, along with SOD released by Mtb, will oxidize INH at sites of infection and their interactions are likely to limit the efficacy of the drug, promote adverse drug reactions via formation of protein adducts, and impair a major bacterial killing mechanism of neutrophils.

Evidence for Limited Genetic Compartmentalization of HIV-1 between Lung and Blood

BackgroundHIV-1 is frequently detected in the lungs of infected individuals and is likely important in the development of pulmonary opportunistic infections. The unique environment of the lung, rich in alveolar macrophages and with specialized local immune responses, may contribute to differential evolution or selection of HIV-1.Methodology and FindingsWe characterized HIV-1 in the lung in relation to contemporaneous viral populations in the blood. The C2-V5 region of HIV-1 env was sequenced from paired lung (induced sputum or bronchoalveolar lavage) and blood (plasma RNA and proviral DNA from sorted or unsorted PBMC) from 18 subjects. Compartmentalization between tissue pairs was assessed using 5 established tree or distance-based methods, including permutation tests to determine statistical significance. We found statistical evidence of compartmentalization between lung and blood in 10/18 subjects, although lung and blood sequences were intermingled on phylogenetic trees in all subjects. The subject showing the greatest compartmentalization contained many nearly identical sequences in BAL sample, suggesting clonal expansion may contribute to reduced viral diversity in the lung in some cases. However, HIV-1 sequences in lung were not more homogeneous overall, nor were we able to find a lung-specific genotype associated with macrophage tropism in V3. In all four subjects in whom predicted X4 genotypes were found in blood, predicted X4 genotypes were also found in lung.ConclusionsOur results support a picture of continuous migration of HIV-1 between circulating blood and lung tissue, with perhaps a very limited degree of localized evolution or clonal replication.

Bordetella pertussis adenylate cyclase toxin (ACT) induces cyclooxygenase‐2 (COX‐2) in murine macrophages and is facilitated by ACT interaction with CD11b/CD18 (Mac‐1)

Bordetella pertussis causes a profound inflammatory response in lungs of infected individuals. The adenylate cyclase toxin (ACT) of B. pertussis is a potent enzyme that converts cytosolic ATP into cAMP, and is required for virulence in vivo. During infection, secreted ACT binds to macrophages utilizing the beta2 integrin, Mac-1 (CR3, CD11b/CD18), and subsequent intoxication by ACT inhibits essential antibacterial activities of macrophages. Additionally, Mac-1 has been reported to be a co-receptor for TLR4 required for the full induction of some LPS-responsive genes, including pro-inflammatory cyclooxygenase 2 (COX-2). We have examined the effect of ACT on COX-2 expression in HEK293T cells expressing Mac-1 and in murine macrophages. We report that ACT induces COX-2 in a manner that absolutely requires the catalytic activity of this enzyme and Mac-1 expression dramatically enhanced the sensitivity of cells to ACT-dependent COX-2 induction. The mechanism of COX-2 induction by ACT utilizes the cAMP-PKA-CREB-dependent pathway. Finally, ACT and TLR2 or TLR4 act synergistically to increase COX-2 expression. These data suggest that ACT contributes significantly to the inflammatory response induced by B. pertussis infection by augmenting COX-2 expression and provides evidence against the concept that ACT functions exclusively via its inhibitory effects on phagocytic leucocytes.

Characterization of the host cell entry of filamentous influenza virus

Most laboratory-adapted strains of influenza virus exist as spheres of approximately 100 nm in diameter, which are well established to enter cells by endocytosis in a pH-dependent manner. However, influenza virus isolated from the lungs of infected individuals is believed to exist as predominantly filamentous particles, up to several micrometers in length. Here, we have attempted an initial characterization of the entry of purified influenza virus filaments into host cells--in comparison to more commonly studied spherical forms of the virus. We demonstrate that the internalization of filamentous influenza virus particles is delayed, relative to spherical particles, and that this delay is a result of morphological rather than strain differences. The filamentous influenza particles appear to retain their dependence on low-pH for entry, as demonstrated by a vacuolar-ATPase inhibitor, and viral trafficking to late endosomes, as demonstrated by the requirement for protein kinase C function. However, our data suggest that the endocytic uptake of the filamentous virus particles may be dynamin-independent, unlike spherical virions. Overall, these data provide a view of the entry of influenza virus in its filamentous morphology, demonstrating potential differences between the endocytosis of spherical virions in vitro and filamentous virions in vivo.