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Malaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8 + T cells with anti-CD8β antibodies in C57BL/6 mice infected with P. berghei ANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8 + T cells into PbA-infected TCRβ −/− mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8 + T cells in an IFNγ−dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8 + T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments. Severe malaria can be associated with respiratory complications. Here, the authors show that malaria-associated pulmonary vascular damage is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8 + T cells induced during infection.

Ascariasis is one of the most common infections in the world and associated with significant global morbidity. Ascaris larval migration through the host’s lungs is essential for larval development but leads to an exaggerated type-2 host immune response manifesting clinically as acute allergic airway disease. However, whether Ascaris larval migration can subsequently lead to chronic lung diseases remains unknown. Here, we demonstrate that a single episode of Ascaris larval migration through the host lungs induces a chronic pulmonary syndrome of type-2 inflammatory pathology and emphysema accompanied by pulmonary hemorrhage and chronic anemia in a mouse model. Our results reveal that a single episode of Ascaris larval migration through the host lungs leads to permanent lung damage with systemic effects. Remote episodes of ascariasis may drive non-communicable lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and chronic anemia in parasite endemic regions.

Background Toxoplasma gondii ( T. gondii ) is an important apicomplexan parasite that causes zoonotic toxoplasmosis in humans and animals. Acute T. gondii infection leads to systemic immunopathology that may manifest as lung injury or pulmonary embolism. Ferroptosis is an iron-dependent regulated cell death driven by lethal lipid hydroperoxide accumulation. Emerging evidence implicates ferroptosis in infection-related tissue damage; however, the role of ferroptosis in T. gondii -induced lung injury remains to be explored. Methods Mice were infected with T. gondii to establish a lung injury model. The body weight changes, survival rate, inflammatory cytokines, lung histopathology, and parasite burden were assessed. The key ferroptosis-related indicators involved in antioxidant, iron metabolism, and lipid metabolism pathways were analyzed in lung tissues using techniques such as transmission electron microscopy, western blotting, and immunohistochemistry. Deferiprone (DFP), an oral iron chelator that can inhibit ferroptosis, was used to investigate the potential role of ferroptosis in T. gondii lung injury. Results T. gondii infection induced lung injury in mice with thickening of alveolar septa and hemorrhage in alveolar spaces, accompanied by iron deposition. Crucially, T. gondii triggered ferroptosis in lung tissues of mice, evidenced by MDA elevation, GSH depletion, total iron and Fe 2+ overload, and mitochondrial cristae loss. Furthermore, iron metabolism pathways were disordered while antioxidant pathways were suppressed. DFP treatment reversed ferroptosis alterations, decreased inflammatory cytokines, attenuated pathological changes, reduced T. gondii burden, and prolonged survival of the infected mice. Conclusions Our findings revealed that T. gondii infection triggered ferroptosis by compromising dysregulated iron metabolism and antioxidant defenses, playing a key role in T. gondii -induced lung injury. DFP exhibited a promising therapy effect for toxoplasmosis. Graphical Abstract

Malaria is an infectious disease caused by Plasmodium that severely impacts human health, often resulting in lung injury. Classical type 2 dendritic cells (cDC2) in the lungs play a crucial role in the pathogenesis of asthma and infectious diseases; however, their specific functions during Plasmodium infection remain poorly understood. In this study, we demonstrated a significant accumulation and activation of cDC2 in the lungs of mice infected with Plasmodium . While the phagocytosis ability of activated cDC2 decreases, it promotes the differentiation of CD4 + T cells towards Th1 cells, thereby exacerbating lung injury. During our investigation into cDC2 accumulation in the lungs, we discovered that this accumulation may occur through autophagy. Furthermore, mechanistic studies revealed that the effect of Plasmodium on cDC2 is mediated by the JAK/STAT3 signaling pathway. Inhibition of STAT3 phosphorylation by the JAK inhibitor JSI-124 almost completely abolished the influence of Plasmodium on cDC2. The role of cDC2 in lung injury induced by Plasmodium infection was further substantiated in IRF4-deficient mice infected with Plasmodium . In conclusion, our research significantly enriches our understanding of lung cDC2, further elucidates the pathogenic mechanisms of Plasmodium infection, and offers a novel theoretical foundation for malaria prevention and control. Schematic model demonstrated that Plasmodium infection suppressed autophagy in lung cDC2 via the TLR3/7-STAT3-IRF4 signaling pathway. Autophagy deficiency caused abnormal accumulation of cDC2 in lungs, impairing their phagocytosis capacity and clearance of malaria parasites. IL-12 secreted by cDC2 drove Th1-biased T-cell differentiation, which exacerbated pro-inflammatory responses and increased immunopathological damage in lung tissues. Inhibition of STAT3 or knockout of IRF4 within cDC2 restored cDC2 autophagy, reduced aberrant accumulation, re-established the phagocytic function of cDC2, and attenuated pro-inflammatory responses of Th1 cells, ultimately alleviating lung inflammatory damage.

Schistosome infection is a major cause of global morbidity, particularly in sub-Saharan Africa. However, there is no effective vaccine for this major neglected tropical disease, and re-infection routinely occurs after chemotherapeutic treatment. Following invasion through the skin, larval schistosomula enter the circulatory system and migrate through the lung before maturing to adulthood in the mesenteric or urogenital vasculature. Eggs released from adult worms can become trapped in various tissues, with resultant inflammatory responses leading to hepato-splenic, intestinal, or urogenital disease – processes that have been extensively studied in recent years. In contrast, although lung pathology can occur in both the acute and chronic phases of schistosomiasis, the mechanisms underlying pulmonary disease are particularly poorly understood. In chronic infection, egg-mediated fibrosis and vascular destruction can lead to the formation of portosystemic shunts through which eggs can embolise to the lungs, where they can trigger granulomatous disease. Acute schistosomiasis, or Katayama syndrome, which is primarily evident in non-endemic individuals, occurs during pulmonary larval migration, maturation, and initial egg-production, often involving fever and a cough with an accompanying immune cell infiltrate into the lung. Importantly, lung migrating larvae are not just a cause of inflammation and pathology but are a key target for future vaccine design. However, vaccine efforts are hindered by a limited understanding of what constitutes a protective immune response to larvae. In this review, we explore the current understanding of pulmonary immune responses and inflammatory pathology in schistosomiasis, highlighting important unanswered questions and areas for future research.

The spectrum of the clinical presentation and severity of malaria infections is broad, ranging from uncomplicated febrile illness to severe forms of disease such as cerebral malaria (CM), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pregnancy-associated malaria (PAM) or severe anemia (SA). Rodent models that mimic human CM, PAM and SA syndromes have been established. Here, we show that DBA/2 mice infected with P. berghei ANKA constitute a new model for malaria-associated ALI. Up to 60% of the mice showed dyspnea, airway obstruction and hypoxemia and died between days 7 and 12 post-infection. The most common pathological findings were pleural effusion, pulmonary hemorrhage and edema, consistent with increased lung vessel permeability, while the blood-brain barrier was intact. Malaria-associated ALI correlated with high levels of circulating VEGF, produced de novo in the spleen, and its blockage led to protection of mice from this syndrome. In addition, either splenectomization or administration of the anti-inflammatory molecule carbon monoxide led to a significant reduction in the levels of sera VEGF and to protection from ALI. The similarities between the physiopathological lesions described here and the ones occurring in humans, as well as the demonstration that VEGF is a critical host factor in the onset of malaria-associated ALI in mice, not only offers important mechanistic insights into the processes underlying the pathology related with malaria but may also pave the way for interventional studies.

Pneumocystis pneumonia (PCP) and pulmonary toxoplasmosis (PT) are caused by Pneumocystis jirovecii and Toxoplasma gondii . The clinical symptoms and imaging of PCP and PT are indistinguishable. A duplex qPCR was developed to differentiate between these two pathogens. In testing 92 clinical samples to validate the performance of this method for P . jirovecii detection, it identified 31 positive samples for P . jirovecii infection, consistent with clinical diagnosis. Among the remainder of the 61 clinical samples with suspected PCP, yet showing as negative by the conventional PCR diagnosis approach, 6 of them proved positive using our new assay. Our new approach also produced similar results in identification of T . gondii infections, giving a result of 2 positive and 20 negative in clinical samples. An investigation was undertaken on the prevalence of P . jirovecii and T . gondii infections using 113 samples from lung infection patients. 9% (10/113) were shown to be positive with infections of P . jirovecii , 2% with T . gondii (2/113) and 5% (6/113) were co-infected with both pathogens. Although this duplex qPCR can detect individual P . jirovecii and T . gondii infection, and co-infection of both pathogens, further large-scale investigations are needed to validate its performance, especially in T . gondii detection. Our assay provides a rapid and accurate tool for PCP and PT diagnosis in immunocompromised population and clinical surveillance of these infections in patients with no immune defects.

In this study, the impact of inhibiting the PI3K/AKT/NF-κB pathway on lung oxidative damage induced by cyst fluid was investigated. Twenty-four mice were randomly assigned to four groups. Three months after inoculation with hydatid cyst segments, mice in group A were treated with intraperitoneal and intratracheal saline injections; mice in group B were administered a caudal vein injection of a PI3K inhibitor, followed by cyst fluid sensitization; mice in group C received an AKT inhibitor via caudal vein, followed by cyst fluid sensitization; and mice in group D were subjected to cyst fluid sensitization without any inhibitor treatment. Cellular changes in lung tissues across all groups were evaluated, including pathological section analysis. Analysis of pulmonary tissue and serum from these mice included the assessment of PI3K/AKT/NF-κB pathway proteins, inflammatory factors, and related mRNA levels. Mice in groups B and C exhibited a higher proportion of M2-type macrophages and significantly lower levels of PI3K/AKT/NF-κB pathway proteins, inflammatory factors (interleukin-6 [IL-6]/tumor necrosis factor-α [TNF-α]), and oxidative markers in lung tissues compared to mice in group D ( 0.05). Our results in this study indicate that activation of the PI3K/AKT/NF-κB pathway contributed to an increase in the M1 macrophage phenotype, leading to enhanced secretion of peroxidases and inflammatory factors. This mechanism plays a crucial role in the oxidative and inflammatory lung damage associated with allergic reactions to cyst fluid.

Dirofilaria nematodes, a common cause of canine filarial disease, are increasingly recognized as emerging human pathogens. We report a case of human pulmonary dirofilariasis in the lung of a man from Northern Australia with pulmonary adenocarcinoma. This case highlights the risk for zoonotic transmission in regions with high canine heartworm prevalence.

Iwasaki and Mezhitov provide an update of their classic 2004 Review looking at the control of adaptive immunity by the innate immune system Microbial infections are recognized by the innate immune system both to elicit immediate defense and to generate long-lasting adaptive immunity. To detect and respond to vastly different groups of pathogens, the innate immune system uses several recognition systems that rely on sensing common structural and functional features associated with different classes of microorganisms. These recognition systems determine microbial location, viability, replication and pathogenicity. Detection of these features by recognition pathways of the innate immune system is translated into different classes of effector responses though specialized populations of dendritic cells. Multiple mechanisms for the induction of immune responses are variations on a common design principle wherein the cells that sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate effector responses. Here we discuss these emerging principles of innate control of adaptive immunity.