Leptospirosis in Animals: Pathogenesis, Renal Tropism, and Zoonotic Implications

Leptospirosis is a globally prevalent bacterial zoonosis caused by pathogenic spirochetes of the genus Leptospira. The disease affects a wide range of mammalian hosts, including domestic livestock, companion animals, and wildlife. The clinical spectrum in animals varies from subclinical infection to acute multi-organ failure, with the kidneys and liver being primary target organs. This review focuses on the spirochete biology, host-adapted versus non-host-adapted serovars, molecular mechanisms of renal and hepatic injury, and environmental persistence. The zoonotic implications are considered from a comparative host-range perspective, emphasizing the role of animal reservoirs.

Spirochete Biology and Classification

Leptospira species are Gram-negative, aerobic, helical spirochetes that possess endoflagella enabling corkscrew-like motility. Taxonomically, the genus is divided into pathogenic (e.g., L. interrogans, L. borgpetersenii, L. kirschneri, L. weilii), intermediate (e.g., L. licerasiae, L. fainei), and saprophytic (e.g., L. biflexa) clades [1]. Recent genomic analyses have expanded the understanding of intraspecies diversity, particularly within pathogenic species [2, 47]. The outer membrane of pathogenic leptospires contains an array of surface-exposed proteins that mediate adhesion, immune evasion, and tissue colonization. These include lipoproteins such as LipL32, LipL41, LipL46, and the immunoglobulin-like proteins LigA and LigB [3, 4, 5, 6, 7]. The lipopolysaccharide (LPS) O-antigen defines serovar specificity and is a major determinant of host adaptation and virulence [8]. Small regulatory RNAs have been identified in L. borgpetersenii serovar Hardjo, and their conservation across the genus suggests roles in gene regulation during host infection [9].

Host-Adapted and Non-Host-Adapted Serovars

A key feature of leptospiral epidemiology is the distinction between host-adapted (maintenance) and non-host-adapted (incidental) serovars. Host-adapted serovars establish chronic, asymptomatic renal carriage in specific reservoir species, whereas non-host-adapted serovars cause acute disease when transmitted to accidental hosts. For example, L. interrogans serovar Copenhageni is maintained by rats (Rattus norvegicus) [10, 11], while L. borgpetersenii serovar Hardjo is adapted to cattle [12, 2]. In one study from Puerto Rico, feral swine and domestic livestock showed seropositivity to multiple serovars, highlighting the role of wildlife as reservoirs [13]. Similarly, rodent and bat populations in Sri Lanka harbor novel sequence types, indicating unrecognized maintenance cycles [11, 14]. Seroprevalence in Lavradeiro horses from the Northern Brazilian Amazon reflects exposure to a range of serovars, likely from environmental contamination [15]. In dogs, both maintenance (e.g., serovar Canicola) and incidental serovars (e.g., serovar Icterohaemorrhagiae) are identified, with risk factors including contact with infected urine and contaminated water [16, 17, 18, 19, 20]. Cats, once considered resistant, are now recognized as susceptible to chronic infection, particularly with serovars shared with rodent reservoirs [21, 19]. A One Health approach in Colombia demonstrated interactions between bovine farms, wildlife, and environmental water sources, emphasizing the complexity of transmission cycles [22].

The genital tract has been identified as a site of persistent colonization in ruminants, often without overt clinical signs. Leptospira spp. have been detected in ovarian structures and the uterus of naturally infected cattle and sheep, potentially impairing reproductive performance [23, 24, 25, 26]. This suggests that venereal transmission may be underappreciated, and that the genital niche may contribute to maintenance in livestock populations [48].

Pathogenesis and Tissue Tropism

Following penetration through mucous membranes or abraded skin, leptospires disseminate hematogenously to target organs. The liver is an early site of bacterial capture and clearance. Recent work using murine models has shown that hepatic macrophages (Kupffer cells) restrict leptospiral dissemination via the C-type lectin receptor Clec4d, which activates C/EBPβ transcription and downstream phagocytic responses [27]. Failure of this mechanism leads to fulminant infection. In dogs, serial evaluation of pulmonary function has revealed that leptospirosis-associated pulmonary hemorrhagic syndrome (LPHS) is a severe complication characterized by endothelial damage and immune complex deposition [28, 29]. Acute pancreatitis has also been described as a rare but notable manifestation [30].

Renal tropism is the hallmark of chronic leptospirosis. Spirochetes adhere to the brush border of proximal tubular epithelial cells via Lig proteins, LipL32, and other adhesins. They then translocate to the interstitium, where they evade immune clearance and establish persistent colonization [5, 31]. The CdaA protein, a diadenylate cyclase, produces cyclic di-AMP, a secondary messenger that may modulate host immune responses during renal infection [32]. Transcriptomic studies in an ovine dialysis membrane chamber model have revealed early gene expression changes in L. interrogans during adaptation to the mammalian environment [12]. In the kidney, leptospires form biofilms that protect them from antibiotics and host immunity, contributing to prolonged shedding in urine. The role of antimicrobial proteins in controlling infection is being elucidated through transcriptomic analyses, which highlight differential expression of host defense peptides [33].

The molecular basis for renal persistence involves both bacterial factors and host immune modulation. Leptospires suppress NF-κB signaling and downregulate MHC class II expression in renal epithelial cells, creating an immunoprivileged niche. Studies using CRISPR-based mutagenesis have confirmed the essentiality of LPS biosynthesis genes, and the O-antigen polymerase Wzm/Wzt appears critical for survival in vivo [8]. In contrast, the LigB protein of L. borgpetersenii serovar Arborea was found to be dispensable for both acute and chronic infection, suggesting functional redundancy among adhesins [5].

Immunopathology and Vaccine Development

The immune response to leptospiral infection is characterized by early innate activation followed by antibody-mediated clearance of extracellular bacteria. However, the spirochete's ability to invade intracellular compartments (e.g., macrophages, endothelial cells) facilitates chronicity. Trained immunity agonists administered to neonatal mice failed to protect against adult challenge and, in some cases, exacerbated disease, indicating that inappropriate immunomodulation can be detrimental [34].

Vaccine development has focused on outer membrane proteins and multi-epitope constructs. Bioinformatics-based identification of B-cell epitopes from the proteins LIC11574 and LIC13411 has enabled rational design of multi-epitope vaccines [3]. A separate immunoinformatics study targeting OMPL1, LipL32, LipL41, and LipL46 reported promising immunogenicity in mouse models [7]. A universal vaccine approach using conserved epitopes across pathogenic species has also been proposed [4]. Oral administration of a Limosilactobacillus strain as a probiotic adjuvant enhanced the efficacy of a whole-cell inactivated vaccine in hamsters, suggesting a role for gut microbiota modulation in vaccination strategies [35].

Environmental Persistence and Epidemiology

Pathogenic leptospires can survive for weeks to months in moist environments, such as surface water, soil, and mud. Survival is enhanced by neutral pH, temperatures above 22°C, and the presence of organic matter. Studies in Argentina detected Leptospira in rodent kidneys and water sources in rural areas, confirming environmental contamination as a transmission pathway [36]. Artificial irrigation in Mediterranean regions significantly influenced the seasonal occurrence of leptospires in wild reservoirs, likely by creating favorable microhabitats [37]. In Colombia, intermediate Leptospira species were found in environmental samples, and their role as potential pathogens remains incompletely understood [1]. Culture media optimization using DMEM and EMEM has demonstrated that pathogenic leptospires can be grown in these alternatives, facilitating isolation from field samples [38].

Diagnostic Approaches

Laboratory diagnosis of leptospirosis in animals relies on serology, molecular detection, and culture. The microscopic agglutination test (MAT) remains the reference serological method, but it is technically demanding and requires a panel of live serovars. Enzyme-linked immunosorbent assays (ELISAs) using recombinant antigens (e.g., LipL32) offer improved standardization and are suitable for herd-level screening [39]. Molecular methods, including conventional PCR and quantitative real-time PCR targeting the lfb1 or 16S rRNA genes, provide early and species-specific detection. High-throughput sequencing enables genotyping and taxonomic classification of isolates, as demonstrated in Colombian environmental and animal samples [1]. Point-of-care molecular diagnostics, similar to those developed for other pathogens, are being adapted for leptospirosis but face challenges related to sample preparation and sensitivity [40].

Table 1 summarizes key virulence factors and their proposed roles in pathogenesis.

Mechanisms of Renal Tropism

Renal colonization is a multistep process. After hematogenous dissemination, leptospires adhere to the basolateral surface of proximal tubular cells via interaction of LigA/LigB with fibronectin and laminin. The bacteria then traverse the intercellular junctions and establish intracellular niches within the tubular epithelium. Once inside, they modulate host cell signaling to avoid lysosomal degradation and promote bacterial replication. The formation of biofilm-like aggregates within the tubules protects leptospires from the flushing action of urine and from host immune cells. Small RNAs expressed by L. borgpetersenii serovar Hardjo may regulate genes involved in biofilm formation and stress responses [9]. The concentration of urea in urine may also induce adaptive responses in leptospires, enhancing their survival.

Recent studies have shown that the bovine genital tract harbors pathogenic leptospires with an uneven distribution across anatomical sites (e.g., oviduct, uterus, cervix) [26]. This suggests that renal tropism may be paralleled by a genital tropism in some host species, with implications for vertical transmission and reproductive failure. The hamster model of genital infection has been used to investigate venereal transmission dynamics [48].

Zoonotic Implications

The zoonotic risk associated with leptospirosis is directly linked to the presence of infected reservoir animals in domestic, peridomestic, and wild environments. Rodents are the most important reservoirs globally, shedding high numbers of leptospires in urine [10, 36, 11]. Dogs can serve as both sentinels and potential sources of human infection, particularly in urban settings [16, 18]. Livestock, including cattle, pigs, and sheep, are significant reservoirs for serovars such as Hardjo, Pomona, and Tarassovi [13, 22, 41, 42]. In Puerto Rico, feral swine were found to harbor multiple serovars, posing a risk to agricultural workers [13]. In South Sudan, Bayesian prevalence estimates among slaughterhouse workers and cattle indicated high occupational risk [41].

One Health surveillance frameworks that integrate human, animal, and environmental health are critical for understanding transmission dynamics and implementing control measures. Multi-sector perspectives from Canada and Colombia highlight the need for coordinated action across veterinary and public health sectors [22, 43]. Urban leptospirosis cases associated with socioeconomic disadvantage in Sydney, Australia, underscore the importance of addressing environmental inequities [10].

The following Mermaid diagram outlines the transmission chain from environmental contamination to animal infection and zoonotic spillover.

graph TD
    A[Environmental contamination: water, soil], >|Survival: weeks to months| B(Maintenance hosts: rodents, livestock, dogs)
    B, >|Renal carriage, shedding in urine| A
    B, >|Direct contact/ contaminated environment| C(Accidental hosts: humans, wildlife)
    C, >|Acute or chronic infection| B
    B, >|Genital colonization| D(Reproductive transmission)
    D, >|Infected offspring/ venereal| B
    A, >|Irrigation, flooding| E(Seasonal amplification)
    E, > B

Conclusion

Leptospirosis in animals is a complex disease driven by the interplay between spirochete virulence factors, host adaptation, and environmental persistence. Renal tropism is central to the maintenance cycle, as chronic carriage leads to urinary shedding and contamination of shared environments. The distinction between host-adapted and incidental serovars is critical for understanding transmission risk and designing targeted interventions. Advances in genomics, immunoinformatics, and diagnostic technology are paving the way for improved vaccines and surveillance tools. A One Health approach, integrating animal health, environmental monitoring, and human exposure, remains essential for reducing the global burden of leptospirosis.

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