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Leptospirosis is a worldwide re-emerging zoonosis caused by pathogenic Leptospira spp. All vertebrate species can be infected; humans are sensitive hosts whereas other species, such as rodents, may become long-term renal carrier reservoirs. Upon infection, innate immune responses are initiated by recognition of Microbial Associated Molecular Patterns (MAMPs) by Pattern Recognition Receptors (PRRs). Among MAMPs, the lipopolysaccha-ride (LPS) is recognized by the Toll-Like-Receptor 4 (TLR4) and activates both the MyD88-dependent pathway at the plasma membrane and the TRIF-dependent pathway after TLR4 internalization. We previously showed that leptospiral LPS is not recognized by the human-TLR4, whereas it signals through mouse-TLR4 (mTLR4), which mediates mouse resistance to acute leptospirosis. However, although resistant, mice are known to be chronically infected by leptospires. Interestingly, the leptospiral LPS has low endotoxicity in mouse cells and is an agonist of TLR2, the sensor for bacterial lipoproteins. Here, we investigated the signaling properties of the leptospiral LPS in mouse macrophages. Using confocal micros-copy and flow cytometry, we showed that the LPS of L. interrogans did not induce internali-zation of mTLR4, unlike the LPS of Escherichia coli. Consequently, the LPS failed to induce the production of the TRIF-dependent nitric oxide and RANTES, both important antimicro-bial responses. Using shorter LPS and LPS devoid of TLR2 activity, we further found this mTLR4-TRIF escape to be dependent on both the co-purifying lipoproteins and the full-length O antigen. Furthermore, our data suggest that the O antigen could alter the binding of the leptospiral LPS to the co-receptor CD14 that is essential for TLR4-TRIF activation. Overall , we describe here a novel leptospiral immune escape mechanism from mouse macro-phages and hypothesize that the LPS altered signaling could contribute to the stealthiness and chronicity of the leptospires in mice.

Leptospirosis is an emerging zoonotic disease with high health and economic damage. In this study, we developed a deterministic mathematical model that describes the dynamics of leptospirosis transmission within a cattle herd, incorporating asymptomatic infected and vaccinated compartments. The study examined the transmission role of asymptomatic cattle that contaminate herds without farmers’ knowledge. We proved the well-posedness of the proposed model and found the basic reproduction number using the next-generation matrix. Analytically, we demonstrated that the disease-free equilibrium point is locally and globally asymptotically stable when R 0 is less than unity and is otherwise unstable. Graphically, we further established the local asymptotic stability of disease-free and endemic equilibria. Sensitivity analysis showed that the contact rate with asymptomatic infected cattle, β A , is the most sensitive parameter in the stated model, followed by the recovery rate of asymptomatic infected cattle, σ , and the vaccination rate of susceptible cattle, τ . Numerical simulations revealed that a reduction in contact rate with asymptomatic infected cattle significantly reduced pathogen Leptospira transmission in the herd. In addition, fostering the recovery rate of asymptomatic infected cattle can significantly reduce new infections in the herd. Furthermore, augmenting the vaccination rate among susceptible cattle resulted in a notable decrease in disease prevalence within the herd. Findings of this study underscore the remarkable importance of targeted interventions, such as reducing contact rates with asymptomatic infected cattle, increasing recovery rates using proper treatments, and enhancing vaccination efforts to manage leptospirosis transmission in cattle herds.

Leptospirosis is a global zoonotic disease affecting humans, wildlife, companion, and domestic animals. Incidental hosts can contract the disease directly or indirectly from asymptomatic reservoir hosts, most commonly small rodents. The Golden Syrian hamster is recognized as the dominant rodent model for acute leptospirosis because the animals are susceptible to many serovars and are used to maintain laboratory strains and test bacterin vaccine efficacy. However, hamsters are primarily used in survival-based studies, and investigations into host immune response and disease pathogenesis are limited. We found that Peromyscus leucopus white-footed deer mice are susceptible to acute leptospirosis, and thus might be an alternative rodent model. Furthermore, similar to hamsters, deer mice produce circulating foamy macrophages in response to Leptospira challenge. Deer mice exhibit differences in response to different serovars, clinical disease severity, kidney and liver lesions, and an overall sex effect, with male mice demonstrating more severe clinical signs and higher bacterial burden.

Leptospira interrogans are pathogenic spirochetes responsible for leptospirosis, a worldwide reemerging zoonosis. Many Leptospira serovars have been described, and prophylaxis using inactivated bacteria provides only short-term serovar-specific protection. Therefore, alternative approaches to limit severe leptospirosis in humans and morbidity in cattle would be welcome. Innate immune cells, including macrophages, play a key role in fighting infection and pathogen clearance. Recently, it has been shown that functional reprograming of innate immune cells through the activation of pattern recognition receptors leads to enhanced nonspecific antimicrobial responses upon a subsequent microbial encounter. This mechanism is known as trained immunity or innate immune memory. We have previously shown that oral treatment with Lactobacillus plantarum confers a beneficial effect against acute leptospirosis. Here, using a macrophage depletion protocol and live imaging in mice, we established the role of peritoneal macrophages in limiting the initial dissemination of leptospires. We further showed that intraperitoneal priming of mice with CL429, a TLR2 and NOD2 agonist known to mimic the modulatory effect of Lactobacillus, alleviated acute leptospiral infection. The CL429 treatment was characterized as a training effect since i.) it was linked to peritoneal macrophages that produced ex vivo more pro-inflammatory cytokines and chemokines against 3 different pathogenic serovars of Leptospira, independently of the presence of B and T cells, ii.) it had systemic effects on splenic cells and bone marrow derived macrophages, and iii.) it was sustained for 3 months. Importantly, trained macrophages produced more nitric oxide, a potent antimicrobial compound, which has not been previously linked to trained immunity. Accordingly, trained macrophages better restrict leptospiral survival. Finally, we could use CL429 to train ex vivo human monocytes that produced more cytokines upon leptospiral stimulation. In conclusion, host-directed treatment using a TLR2/NOD2 agonist could be envisioned as a novel prophylactic strategy against acute leptospirosis.

Serology (the detection of antibodies formed by the host against an infecting pathogen) is frequently used to assess current infections and past exposure to specific pathogens. However, the presence of cross-reactivity among host antibodies in serological data makes it challenging to interpret the patterns and draw reliable conclusions about the infecting pathogen or strain. In our study, we use microscopic agglutination test (MAT) serological data from three host species [California sea lion (Zalophus californianus), island fox (Urocyon littoralis), and island spotted skunk (Spilogale gracilis)] with confirmed infections to assess differences in cross-reactivity by host species and diagnostic laboratory. All host species are known to be infected with the same serovar of Leptospira interrogans. We find that absolute and relative antibody titer magnitudes vary systematically across host species and diagnostic laboratories. Despite being infected by the same Leptospira serovar, three host species exhibit different cross-reactivity profiles to a 5-serovar diagnostic panel. We also observe that the cross-reactive antibody titer against a non-infecting serovar can remain detectable after the antibody titer against the infecting serovar declines below detectable levels. Cross-reactivity in serological data makes interpretation difficult and can lead to common pitfalls. Our results show that the highest antibody titer is not a reliable indicator of infecting serovar and highlight an intriguing role of host species in shaping reactivity patterns. On the other side, seronegativity against a given serovar does not rule out that serovar as the cause of infection. We show that titer magnitudes can be influenced by both host species and diagnostic laboratory, indicating that efforts to interpret absolute titers (e.g., as indicators of recent infection) must be calibrated to the system under study. Thus, we implore scientists and health officials using serological data for surveillance to interpret the data with caution.

•It is the first time that the specific IgY recognized and bound to Leptospira could be extracted from vaccinated hens.•Specific IgY can cure Leptospira-infected hamsters at either early or late stages.•Treatment with specific IgY protected Leptospira-infected hamsters from renal colonization.•Specific IgY was able to directly inhibit the growth of Leptospira. Leptospirosis, a globally significant zoonotic disease caused by pathogenic Leptospira, continues to threaten the health and public safety of both humans and animals. Current clinical treatment of leptospirosis mainly relies on antibiotics but their efficacy in severe cases is controversial. Passive immunization has a protective effect in the treatment of infectious diseases. In addition, chicken egg yolk antibody (IgY) has gained increasing attention as a safe passive immunization agent. This study aimed to investigate whether hens produce specific IgY after immunization with inactivated Leptospira and the protective effect of specific IgY against leptospirosis. First, it was demonstrated that specific IgY could be extracted from the eggs of hens vaccinated with inactivated Leptospira and that specific IgY can specifically recognize and bind homotypic Leptospira with a high titre, as shown by MAT and ELISA. Next, we tested the therapeutic effects of IgY in early and late leptospirosis using a hamster model. The results showed that early specific IgY treatment increased the survival rate of hamsters to 100%, alleviated pathological damage to the liver, kidney, and lung, reduced leptospiral burden, and restored haematological indices as well as functional indicators of the liver and kidney. The therapeutic effect of early specific IgY was comparable to that of doxycycline. Late IgY treatment also enhanced the survival rate of hamsters and improved the symptoms of leptospirosis similar to early IgY treatment. However, the therapeutic effect of late IgY treatment was better when combined with doxycycline. Furthermore, no Leptospira colonization was observed in the kidneys, livers, or lungs of the surviving hamsters treated with specific IgY. Mechanistically, IgY was found to inhibit the growth and adhesion to cells of Leptospira. In conclusion, passive immunotherapy with specific IgY can be considered an effective treatment for leptospirosis, and may replace antibiotics regarding its therapeutic effects.

Golden Syrian Hamsters are utilized as rodent research models for various bacterial diseases. They are highly susceptible to leptospirosis, making hamsters the most common model for testing and maintaining virulence of laboratory Leptospira strains as well as for bacterin vaccine efficiency testing. Hamsters are also used for modeling features of Bacillus Calmette–Guérin (BCG) and tuberculosis, as they consistently develop granulomas, differing from other BCG animal models. Circulating foamy macrophages have recently been identified in the blood of the hamsters following Leptospira challenge but not in controls. It has been unknown whether this phenomenon is specific to Leptospira/hamster interactions, or whether hamsters will produce circulating foamy macrophages in response to other bacterial infections. In this study, we established that hamsters develop circulating foamy macrophages when challenged intraperitoneally with BCG or Leptospira. In addition to circulating foamy macrophages, hamsters infected with BCG had widespread granuloma formation in major organs and injection sites which also contained resident foamy macrophages, as well as mineralized bodies, sometimes containing acid fast bacteria. Pictured are representative images of Giemsa-stained whole blood smear containing foamy macrophages and photomicrograph of mesenteric lymph node from a hamster infected I.P. with M. bovis BCG and examined 40 days later. Note granulomas composed of centrally located foamy macrophages, macrophages, and lesser numbers of lymphocytes. [Display omitted] •Golden Syrian Hamsters are critical animal models for vaccine testing.•Hamsters produce granulomas in response to BCG vaccination.•In response to BCG vaccination hamsters produce circulating foamy macrophages.•Foamy macrophages could play a role in disease pathogenesis.

Leptospirosis is a neglected tropical zoonosis caused by pathogenic spirochetes of the genus . Infected reservoir animals, typically mice and rats, are asymptomatic, carry the pathogen in their renal tubules, and shed pathogenic spirochetes in their urine, contaminating the environment. Humans are accidental hosts of pathogenic . Most human infections are mild or asymptomatic. However, 10% of human leptospirosis cases develop into severe forms, including high leptospiremia, multi-organ injuries, and a dramatically increased mortality rate, which can relate to a sepsis-like phenotype. During infection, the triggering of the inflammatory response, especially through the production of cytokines, is essential for the early elimination of pathogens. However, uncontrolled cytokine production can result in a cytokine storm process, followed by a state of immunoparalysis, which can lead to sepsis and associated organ failures. In this review, the involvement of cytokine storm and subsequent immunoparalysis in the development of severe leptospirosis in susceptible hosts will be discussed. The potential contribution of major pro-inflammatory cytokines in the development of tissue lesions and systemic inflammatory response, as well as the role of anti-inflammatory cytokines in contributing to the onset of a deleterious immunosuppressive cascade will also be examined. Data from studies comparing susceptible and resistant mouse models will be included. Lastly, a concise discussion on the use of cytokines for therapeutic purposes or as biomarkers of leptospirosis severity will be provided.

Early diagnosis of leptospirosis is critical for timely treatment and effective disease management. This study evaluated the diagnostic performance of a novel electrochemical aptasensor targeting the electron transfer flavoprotein subunit beta (EtfB) of Leptospira interrogans in clinical samples collected during the acute phase of leptospirosis. The aptasensor assay was tested using plasma samples and compared to the microscopic agglutination test (MAT), the standard reference method. To assess diagnostic performance, aptasensor results were evaluated against leptospirosis status as determined by MAT. Receiver operating characteristic (ROC) analysis identified a 40% decrease in electrochemical signal relative to the blank as the optimal cut-off, yielding an area under the curve (AUC) of 0.93. The assay demonstrated a sensitivity of 100% and a specificity of 80%. For diagnostic concordance, aptasensor results were compared with those obtained from the reference quantitative PCR (qPCR) method. The aptasensor exhibited 100% positive agreement and 57.1% negative agreement with qPCR. Notably, in patients with high MAT titers, the aptasensor outperformed qPCR in detection rates (100% vs. 25%). These findings indicate that the aptasensor assay is a highly reliable and effective antigen-based diagnostic tool for early leptospirosis detection, making it suitable for both low- and high-prevalence settings.

Leptospirosis is a globally distributed zoonosis with multisystemic involvement in canine species, capable of causing a pulmonary hemorrhagic syndrome (LPHS) in the most severe cases. In humans, the neutrophil to lymphocyte ratio (NLR), platelets to lymphocytes (PLR) and systemic immune-inflammation index (SII) have been described as predictors of morbidity and mortality in various pathologies, but no such studies have been developed for canine leptospirosis. Hence, we aimed to assess the usefulness of NLR, PLR and SII in dogs affected with leptospirosis, focusing on those that died or survived after hospitalization, whether or not they developed LPHS. The leptospirosis group was composed by 36 dogs while the control group consisted of 32 healthy dogs. The NLR, associated with inflammation, demonstrated a threefold or greater increase in all leptospirosis groups compared to the control group (median 2.44 ± 1.66) (developing or not LPHS). Dogs that died (median 67.78 ± 158.67), developed LHPS (median 85.17 ± 143.77), or both developed LHPS and died (median 67.78 ± 155,14) had a lower PLR in comparison to the control group (median 101,82 ± 53,75) and the rest of groups, but no statistically significant differences were observed (p > 0.05). The SII was higher in leptospirosis-affected dogs that survived (median 1356,92 ± 2726,29) and statistically significant differences were observed in those who did not develop LPHS (median 1770,41 ± 2630,77; p < 0.05) compared to the control group (median 555,21 ± 313,26). Our data shows that NLR may be used as inflammation indicator, while more studies are needed for PLR and SII in canine leptospirosis.