Ras signalling is an important regulator of cell proliferation, survival, differentiation, and immune responses. Although Ras pathways have been extensively studied in cancer biology, increasing evidence suggests that many pathogens also manipulate Ras-associated signalling networks to support infection, persistence, and immune evasion. Viruses, bacteria, and parasites can alter Ras activity either directly or indirectly through downstream pathways such as MAPK/ERK and PI3K/AKT. However, activation of ERK or AKT does not always indicate direct Ras involvement, and this distinction remains important in infectious disease research. Recent studies show that pathogens including SARS-CoV-2, Epstein-Barr virus, hepatitis B virus, Helicobacter pylori, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Leishmania species regulate Ras-associated signalling in ways that contribute not only to pathogen survival but also to inflammation, tissue injury, and disease progression. In several infections, isoform-specific regulation of H-Ras, K-Ras, and N-Ras has also been observed, suggesting distinct roles in immune modulation and pathological outcomes. Dysregulated Ras-associated signalling has been linked to lung injury, liver fibrosis, gastric epithelial damage, granuloma formation, and systemic dissemination of infection. This review summarizes current evidence on the role of Ras signalling in infectious disease pathology, focusing on host-pathogen interactions, isoform-specific regulation, tissue damage, and therapeutic implications. Although Ras signalling represents a promising host-directed target, much of the current evidence remains indirect and requires further pathogen-specific validation.

Animal tuberculosis caused by mycobacteria of the Mycobacterium tuberculosis complex (MTBC) represents a significant challenge to both public and animal health. Although eradication programs focus predominantly on cattle, small ruminants, especially goats, may play a relevant role as reservoirs. This study aimed to characterize tuberculosis cases in small ruminants in Portugal diagnosed at the national reference laboratory for Tuberculosis (Instituto Nacional de Investigação Agrária e Veterinária) over the period from April 2012 to July 2023. In this study, samples from 79 animals suspected of TB (64 goats and 15 sheep) were analyzed by integrating histopathology; bacteriology; and, when applicable, PCR results, thereby allowing the distribution by species to be described, MTBC agents to be identified, and diagnostic agreement to be assessed. Of these samples, 29 positive cases (36.7%) were identified, all of them in goats (45.3% of goats tested), whereas no cases were confirmed in sheep. Mycobacterium caprae was the most frequently identified species (89.7%), followed by Mycobacterium bovis (10.3%). Geographic distribution was concentrated in the Alentejo (48.3%) and Norte (44.8%) regions, where 93.1% of cases occurred. Topographical analysis of lesions revealed respiratory tract involvement (lung and/or thoracic lymph nodes) in 82.7% of positive cases, with gross patterns including caseous/caseocalcified lesions (n = 11), necrosis (n = 9), and nodular granulomatous lesions (n = 10). Agreement between histopathology and bacteriology was 81.5%. Parasitic coinfections were observed in 24.1% of positive cases, complicating histopathological interpretation. The results of this study indicate goats, as opposed to sheep, as non-negligible reservoirs of TB, suggesting species-level differences that warrant targeted investigation. The predominance of respiratory lesions and the detection of extensive cavitary forms indicate potential aerogenous transmission with implications for multi-host systems. Diagnostic discordance and parasitic interference reinforce the need for combined testing methodologies. It is therefore advisable to consider the integration of goats into tuberculosis surveillance and control programs, with greater relevance in Alentejo and Norte.

Local immune cell activation and vascular remodelling are characteristic pathogenic features of pulmonary arterial hypertension (PAH). HIV and schistosome infections have been individually associated with PAH. However, whether co-infection with these pathogens has a distinct impact on the development of pulmonary vascular disease remains poorly understood, partly due to the lack of experimental animal models. In a novel non-infectious model of HIV and Schistosoma pulmonary co-exposure based on lung embolisation of S. mansoni eggs in HIV-transgenic (HIV) mice, we previously reported exacerbated endothelial remodelling and dysfunction, along with increased pulmonary arterial pressure; which were associated with a unique profile of pro-inflammatory cytokines in the lung. In the present study, we used flow cytometric analysis of isolated lung leukocytes and immunofluorescence staining to characterise the pulmonary immune cell landscape associated with individual or combined exposure to HIV and schistosome. Compared with mice exposed to HIV (untreated HIV mice) or schistosome (egg-treated wild-type mice), co-exposed (egg-treated HIV mice) animals showed significantly increased numbers of interstitial and alveolar macrophages, patrolling-type monocytes, NKT and γδ T cells, and reduced CD8[+] αβ T cells. Other lung immune cells, including inflammatory-type monocytes, eosinophils/neutrophils, dendritic cells, CD4[+] αβ T cells, NK cells and B cells were not significantly affected in the co-exposure condition. Taken together, these results show for the first time that combined pulmonary exposure to HIV and Schistosoma, as it may occur in co-infected individuals, alters the local immune cell landscape in a manner distinct from that of individual exposure. Furthermore, these findings may contribute to a better understanding of the complex inflammatory processes involved in the pathogenesis of PAH, thereby supporting the development of therapies targeting pathogenic immune cells in pulmonary vascular disease associated with HIV and Schistosoma co-morbidity.

Atopic diseases arise from an immunological imbalance where regulatory mechanisms are unable to preserve or restore homeostasis, leading to chronic inflammatory conditions affecting epithelial organs. This may involve homeostasis, deficient or insufficient regulatory T cells (Tregs) or other aberrant regulatory mechanisms. Type 2 (T2) immunity is a conserved response that evolved to combat large helminth parasites (worms), venoms, and toxins involving both innate and adaptive immune pathways. Many T2 cytokines and alarmins act to recruit and activate innate and adaptive immune cells, and they also lead to mucous production, hyperplasia, and tissue remodeling. These responses were designed to enhance expulsion of parasites, repair the barrier and elicit protective mechanical reflexes such as scratching or coughing. Today, with reduced parasitic exposure serving as an opposing influence on T2 immunity, it is hypothesized that T2 responses may be triggered by low amounts of environmental stimuli in genetically susceptible individuals, leading to unchecked T2 inflammation and atopic diseases at multiple barrier surfaces. This paper reviews the evidence linking host T2 immunity with T2 inflammatory mechanisms in atopic diseases and explores the hypothesis that these diseases may be perpetuated from a central imbalance between Th2 vs. Th1, Th3, and Tregs, influenced by tissue-dependent, local environmental-insult-driven innate cell responses, interconnected by a cycle of self-amplifying cytokine signaling.

Visceral leishmaniasis (VL) is a systemic parasitic disease that predominantly involves the reticuloendothelial system, with pulmonary involvement being distinctly uncommon, particularly in individuals who are immunocompetent. We report a case of a middle-aged female who was immunocompetent presenting with acute hypoxaemic respiratory failure, characterised by progressive dyspnoea, bilateral lung consolidation and pleural effusion, initially mimicking severe pulmonary infection or haematological malignancy. The presence of pancytopenia, hypergammaglobulinaemia and massive hepatosplenomegaly raised suspicion of an underlying systemic disorder. Definitive diagnosis was established by demonstration of Leishmania donovani amastigotes in splenic aspirate, with further confirmation of direct pulmonary involvement through identification of intracellular amastigotes within alveolar macrophages on a transbronchial lung biopsy. The patient showed significant clinical and radiological improvement following treatment with liposomal amphotericin B and miltefosine. This case highlights that VL can rarely present with primary pulmonary manifestations even in immunocompetent hosts. It underscores the importance of considering VL in the differential diagnosis of unexplained pulmonary infiltrates with systemic features in endemic regions and demonstrates that histopathological confirmation from lung tissue can be crucial in establishing pulmonary involvement in atypical presentations.

MicroRNA-17(miR-17) is a prototypical oncogenic miRNA that plays a central driving role in the initiation and progression of various malignant tumours (MT), including lymphoma, lung cancer, colorectal cancer (CRC), and breast cancer (BC). It inhibits the activation of apoptosis pathways and promotes the G1/S phase transition by targeting tumor suppressor genes and cell cycle regulators, thereby driving the unlimited proliferation of tumor cells. Concurrently, it targets molecules associated with epithelial-mesenchymal transition (EMT), activating key signalling pathways, such as Phosphatidylinositol 3-Kinase/Protein Kinase B (PI3K/AKT) and Wnt/Beta-catenin(Wnt/β-catenin) to enhance the invasiveness and migration capabilities of tumour cells. Moreover, miR-17 participates in a cross-regulatory network of non- coding RNAs(ncRNAs), acting both as a molecular sponge to sequester long non-coding RNAs(lncRNAs) and circular RNAs(circRNAs), and as a regulator of the stability or biogenesis of these ncRNAs.This further amplifies oncogenic effects, induces tumor cell resistance to chemotherapy and radiotherapy, and ultimately synergistically promotes tumor angiogenesis, thereby remodeling the tumor microenvironment(TME). In clinical applications, miR-17 holds potential for early cancer diagnosis, particularly serving as a non-invasive biomarker in lung and Gastric cancers (GC). As a therapeutic target, restoring miR-17 expression via targeted interventions enhances. The efficacy of chemotherapy or targeted therapy thereby improves patient prognosis. Despite extensive research in this field, the precise mechanism of action for miR-17 remains incompletely understood. This review summarizes the current state of research concerning the relationship between miR-17 and its target genes in MT, as well as the underlying mechanisms involved.

Mycoplasma ovipneumoniae is an important respiratory pathogen in sheep, commonly implicated in chronic pneumonia. Although widely reported, data on its occurrence, strain diversity and the relationship between upper respiratory tract carriage and pulmonary infection remains limited. The study examined a conventional flock of 230 Merino x Berrichon du Cher ewes. Thirty-eight sheep underwent physical examination and nasal swabbing, including 15 animals with additional post-mortem lung sampling. Additionally, lungs from 15 further sheep were examined, yielding 30 lung samples for gross and histopathological assessment. Microbiological examination was performed using cultivation procedures and isolates were identified by applying MALDI-ToF mass spectrometry. Genetic diversity of M. ovipneumoniae strains was assessed using a newly established core genome MLST scheme. Clinical findings were consistent with respiratory disease, and lung lesions were compatible with M. ovipneumoniae-associated pneumonia. M. ovipneumoniae was cultivated from all 38 nasal swabs (100%) and from 27 of 30 lung samples (90%). Cultivation of lung samples identified three principal pathogens: M. ovipneumoniae, Pasteurella multocida, and Mannheimia haemolytica, with concurrent detection observed in a subset of cases. Core genome sequence-based typing indicated both high genetic diversity and the clonal spread of individual M. ovipneumoniae strains on the farm. This study documents M. ovipneumoniae infection in an Austrian sheep flock and highlights the frequent involvement of co-pathogens and the high genotypic diversity of circulating strains. These findings underscore the importance of targeted surveillance, molecular characterisation, and integrated control measures to mitigate respiratory disease. Further multi-farm and longitudinal studies are warranted to clarify transmission dynamics and the clinical significance of strain variation.

Ticks are ectoparasites that modulate host responses to sustain prolonged blood feeding, and in Ixodes ricinus, salivary microRNAs (miRNAs) represent promising candidates for manipulating host gene expression. Using phylogenetic footprinting combined with cooperative targeting analysis, we predicted deeply conserved miRNA-mRNA interactions that appear to contribute to tick lifecycle completion and tick's ability to parasitize diverse vertebrate hosts. Our analysis suggests that conserved tick miRNAs may mimic host miRNAs by exploiting shared target sites on host transcripts, potentially influencing regulatory circuits active during tick feeding and cross-kingdom communication. We identified 12 core tick salivary miRNAs-highly expressed and enriched in conserved target sites-predicted to cooperatively target 22 human genes, several of which are associated with processes relevant to parasitism establishment. These predicted cooperative interactions involve hub genes such as PDGFRA and NRG1, which are components of MAPK and PI3K-AKT pathways that regulate immune defense, tissue repair, and sensory responses. Our results suggest that I. ricinus miRNAs could potentially influence host homeostasis through cooperative targeting mechanisms, and they introduce a broadly applicable framework that leverages evolutionary conservation to detect meaningful cross-species miRNA-mRNA interactions.

Cysteine cathepsins are papain-like proteases which play key roles in a large range of organisms, including apicomplexan parasites. These obligate endoparasites are responsible for many devastating diseases in human and/or animal hosts, for which available treatments are limited or face the emergence of resistance. This review presents the cysteine cathepsins expressed by five major Apicomplexa (Plasmodium falciparum, Cryptosporidium parvum, Toxoplasma gondii, Eimeria tenella and Babesia bovis), highlighting available data on their structures, specific or common features, and biological functions in the parasite biology and host-parasite interactions. Although they belong to the same phylum, apicomplexan parasites have very distinct life cycles and biology, which are well adapted to the hosts they infect and to the tissues within which they develop. Accordingly, apicomplexan cysteine cathepsins display a wide variety of functions, associated with shared (e.g., invasion of and egress from host cells) or unique (e.g., degradation of haemoglobin in P. falciparum) biological pathways. Through their crucial functions and involvement in multiple parasite stages, these parasitic proteases represent assumed therapeutic targets. The description of apicomplexan cysteine cathepsins also appears uneven within the phylum, and further exploration of their biology and role is needed to drive novel preventive or curative intervention strategies.