Search Results (76)

The problem: Johne’s disease, caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP), can be widespread in cattle herds. As a consequence of the slow progression of the infection and the delayed appearance of a humoral response, at any time few of the infected animals may be detected as positive with current serological tests. Many disease control initiatives have focused on removing infected animals by using serology to detect antibodies, principally to a purified MAP extract. However, the delayed humoral response to MAP extract, which can be preceded by shedding MAP in the faeces, limits the value of this control method. The approach: We used a longitudinal study to evaluate the timing and magnitude of antibody responses to lipid antigens. The method: Thirty breeding females from a beef cow herd with a history of Johne’s disease were recruited at 10–12 months old. Blood (serum) and faecal samples were collected at six-month intervals over five years. The serum samples were evaluated by enzyme-linked immunosorbent assay (ELISA) using six synthetic lipid antigens, each from a different class of chemical compound that are components of the mycobacterial cell wall. The responses were correlated with MAP infection status as determined by faecal culture, a commercial serum antibody ELISA (ID Screen^®), and interferon-γ release assays. Nineteen animals were positive using either culture or ID Screen^® at one or more time points; eleven animals were never positive in either assay. Results: In the lipid ELISA, the median responses for all animals were significantly higher at time point 5 (when the animals were three years old) than those at earlier time points. The timing of this response is compatible with, but does not prove, a shift in immune-response profile. For the antigens MOD171 and RT237F2, the responses for each individual animal were higher at time point 5 than at time point 4. Outcome: The increase in response to lipid antigens MOD171 and RT237F2 between the ages of two and four years may indicate infection with MAP at an earlier stage than is achieved with the established serology tests. Full article

Crohn’s disease (CD) is a chronic inflammatory bowel disease with a rising incidence and prevalence worldwide. It is associated with Mycobacterium avium subspecies paratuberculosis (MAP). Current CD treatment strategies are based on anti-inflammatory therapies, including anti-TNF-α drugs. These treatment options provide short-term benefits and are associated with numerous side effects in CD patients. Manuka honey is distinguished from other honey by its high content of methylglyoxal (MGO). MGO, a reactive metabolite, is also generated endogenously in macrophages during infection through glycolysis; however, the amount is insufficient to neutralize the ongoing infection and subsequent tissue damage. This study examined whether exogenous, low-dose MGO can modulate MAP-driven inflammatory and glycolysis- and lactate-associated markers in infected macrophages. THP-1 macrophages were infected with the CD-associated MAP strain and then treated with MGO doses at defined time intervals. We measured markers of M1-/M2-like phenotype polarization, monocarboxylate transporters, lactate export, antioxidant responses, cytokines, and selected glycolysis- and lactate-associated markers at both the mRNA and protein levels. MGO reduced M1 signaling markers CXCL10 (p < 0.05), TNF-α (p < 0.0001), IL-1β (p < 0.01), and IL-6 (p < 0.0001). Simultaneously, MGO promoted M2 shift, elevating CD206 by 1.20-fold and IL-10 by 7-fold. Low-dose MGO administration was associated with increases in Nrf-2 (1.4-fold), HO-1 (1.4-fold), and IL-1Ra (1.5-fold), while the pro-inflammatory cytokines decreased. Metabolically, MGO downregulated MCT4 (p < 0.01) and reduced lactate export by 30%. These changes were coupled with higher PHD2 (1.4-fold) and decreases in GLUT1 (0.9-fold), PKD1 (0.8-fold), and IL-1β, consistent with attenuated glycolysis- and lactate-associated inflammatory signaling. These results suggest that hormetic concentration of MGO mitigates MAP-induced inflammatory activation while altering glycolysis- and lactate-related signaling markers in infected macrophages. Most importantly, we unraveled the predicted molecular mechanism by which MGO suppresses inflammation and modulates oxidative damage. Full article

Johne’s disease (JD), caused by Mycobacterium avium subsp. paratuberculosis (MAP), is typically acquired early in life, yet detection of exposure during this period remains challenging. This study evaluated whether MAP-specific antibodies are passively transferred from dam to calf and detectable in neonatal calf serum, and whether these titres reflect early-life exposure to MAP. Neonatal calves (n = 38) from a commercial dairy herd were blood sampled within the first 10 days of life as part of routine assessment of passive transfer. Serum total protein (STP) was measured to assess colostrum intake, and residual serum was analysed for MAP antibody titres using an indirect ELISA. Multivariable linear regression was used to evaluate associations between calf MAP antibody titres, STP, and dam JD serological status. Calf serum MAP antibody titres were positively associated with STP (p < 0.001) and differed according to dam serological status, with higher titres observed in calves born to MAP-seropositive dams (p = 0.025). A significant interaction between STP and dam status indicated that the relationship between passive transfer efficiency and MAP antibody levels varied by dam infection status. These findings support the biological plausibility of passive transfer of MAP-specific antibodies via colostrum and suggest that neonatal calf serology may reflect exposure to an early-life epidemiological risk period associated with maternal MAP exposure and the calving environment rather than infection status within the calf itself. Given the modest sample size and single-herd design, these findings should be interpreted as exploratory and hypothesis-generating. Full article

The rising incidence of early-onset colorectal cancer (CRC) remains incompletely explained despite extensive investigation into genetic, environmental and metabolic factors. Emerging evidence suggests that infectious agents may contribute to colorectal carcinogenesis. A recent study by Tehrani et al. demonstrated the presence of Mycobacterium avium subspecies paratuberculosis (MAP) in a majority of colorectal cancer lesions and in approximately half of precancerous lesions, providing a critical epidemiologic anchor. MAP, a zoonotic intracellular pathogen long associated with Crohn’s disease, exhibits biological features consistent with inflammation-driven carcinogenesis, including persistence, immune modulation and systemic dissemination. Mechanistically, MAP infection may promote tumorigenesis through chronic mucosal inflammation, epithelial barrier disruption and activation of human endogenous retroviruses (HERVs) linking persistent infection to genomic instability. Detection of MAP in early lesions argues against secondary colonization and supports a potential initiating or promoting role. Within a One Health framework, MAP represents a plausible, pleiotropic and potentially modifiable contributor to CRC. While causality remains unproven, the convergence of epidemiologic association, mechanistic plausibility and early lesion involvement warrants rigorous investigation. Full article

Background/Objectives: Mycobacterial infections and autoimmune diseases affect many worldwide, and growing evidence suggests that there is a bidirectional relationship. This review examines mechanisms by which various autoimmune diseases predispose patients to mycobacterial infections, and vice versa. Methods: We conducted a PubMed/MEDLINE search using the keywords “mycobacterium” and the names of the autoimmune conditions to identify relevant papers. Results: Rheumatoid arthritis therapies, especially TNF-α inhibitors, raise tuberculosis (TB) and non-tuberculous mycobacteria (NTM) risk. Type 1 diabetes features impaired cell-mediated immunity and macrophage dysfunction, with evidence for Mycobacterium avium subspecies paratuberculosis (MAP) mimicry involving HSP65–GAD65. In systemic lupus erythematosus, immune dysregulation plus corticosteroids and cytotoxins elevates TB and NTM risk, amplified in endemic settings. In multiple sclerosis, heightened TLR2/4/9 signaling agents that inhibit pyrimidine synthesis may increase IL-10 and reduce antimycobacterial immunity. Crohn’s disease shows genetic susceptibility (e.g., NOD2 variants) and MAP detection, supporting impaired clearance of intracellular mycobacteria. Conclusions: Overall, evidence supports a bidirectional relationship: mycobacterial antigens can initiate or amplify autoimmunity via molecular mimicry and chronic stimulation, while autoimmune biology and iatrogenic immunosuppression increase susceptibility to infection. Implications include latent TB screening before immunosuppression, attention to local epidemiology, and vigilance for NTM. Research priorities include prospective cohorts, mechanistic studies of mimicry and NOD2–TLR pathways, safety registries, and trials of screening and prophylaxis. Full article

Inflammatory bowel disease (IBD) comprises mainly Crohn’s disease (CD) and Ulcerative Colitis (UC). The Western model suggests that environmental factors, immunological factors, the gut microbiome, and genetic disposition all contribute to the onset and sustained symptoms that define CD, although the pathogenesis of CD remains unresolved. Current studies propose that in individuals who are genetically susceptible, genetic factors linked to immune dysregulation, in combination with environmental exposure, can result in dysbiosis of the gut microbiome and intestinal barrier dysfunction, leading to immune dysregulation. In Malaysia, the incidence of IBD is rising with CD increasing disproportionally compared to UC, and the incidence of CD currently mirrors that of the United Kingdom in the 1930s, which now has one of the highest incidences worldwide. Given the suggested role of Mycobacterium avium subspecies paratuberculosis (MAP) in CD in Western countries, which is subject to some controversy, this review summarises for the first time the current evidence on genetic, environmental, and microbial factors that could contribute to the rise of Crohn’s disease in Malaysia and proposes preventive approaches. We note the increasing reliance of Malaysia on imported cattle and milk products from areas of high Johne’s Disease prevalence to meet increasing demand and changes in milk preferences in the Malaysian population, both key indicators for human-MAP exposure in the Western model. Therefore, should MAP be shown to be associated with CD in Malaysia, some preventative measures are suggested, such as screening imported and native beef and dairy cattle, dairy products and ultimately water, both recreational and potable. Full article

Attenuated Salmonella strains offer an opportunity for delivering DNA vaccines to antigen-presenting cells. DNA vaccines trigger cellular immune responses, making them suitable for targeting intracellular pathogens, such as Mycobacterium avium subspecies paratuberculosis (MAP). Since whole organism MAP vaccines interfere with tuberculosis diagnosis, innovative vaccine technologies have been introduced to elicit an immune response targeting species-specific antigens. Fibronectin attachment protein (FAP), a MAP surface antigen that is species-specific, can induce cellular immune responses. The present study aims to explore the immunogenic potential of a mammalian expression plasmid encoding the fap-P gene of MAP within a mouse model, utilizing a Salmonella vector for oral immunization using a fluorescent assay and Western blot analysis. The results proved the ability of the constructed plasmid to stimulate the humoral immune response in mice. Moreover, fluorescence microscopy of splenocytes confirmed the successful delivery of the plasmid to the immune system at 24, 48, and 72 h following oral administration. It can be concluded that FAP-P could be considered a candidate for further investigation in the context of MAP vaccine development. Additionally, the use of Salmonella as a delivery system not only improves the efficacy of DNA vaccines but also helps in the preliminary evaluation of the antigens’ immunogenic properties. Full article

Paratuberculosis is a chronic zoonotic bacterial infection, primarily affecting ruminants. This review examines the disease in the Arabian Peninsula, focusing on distribution, molecular diversity, prevalence, and associated risk factors. Following PRISMA guidelines, a systematic search was conducted in PubMed, Scopus, and Web of Science. After duplicate removal and eligibility screening, data extraction, analysis, and quality assessment were performed. Pathogen sequences were retrieved from NCBI GenBank for phylogenetic analysis. The review included a total of 31 published articles from 1997 to 2025, of which 26 were used in the meta-analysis. Most studies (n = 12) were published between 2011 and 2015, predominantly from Saudi Arabia (n = 22), with no reports from Qatar, Bahrain, or Yemen. The majority of the studies involved camels and sheep (n = 16 on each species), followed by cattle (n = 9), goats (n = 7), humans (n = 2), and buffalo (n = 1). Phylogenetic analysis delineates two major clades—Type S and Type C—suggesting greater genetic diversity in Type S. The estimated pooled seroprevalence and pathogen prevalence in livestock ruminants were 8.1% and 22.4%, respectively. Herd-level estimated pooled seroprevalence was 26.9%. Small ruminants (19.3%) were more sero-prevalent than large ruminants (7.4%), with goats (28.7%) significantly (p < 0.01) more affected than sheep (21.5%), camel (9.8%), and cattle (6.6%). Clinical signs in ruminants included chronic diarrhea, emaciation, anorexia, alopecia, wry neck, and dehydration. The reviewed study patterns and findings suggest high pathogen diversity and a significant risk of transboundary transmission at the human–animal interface in this region. A One Health surveillance approach is crucial, particularly on farms with diarrheic and emaciated animals. Establishing a national surveillance plan and phased (short-, intermediate-, and long-term) control programs is essential to mitigate economic losses, limit transmission, overcome the cultural barrier, and protect public health. Full article

Paratuberculosis, caused by Mycobacterium avium subspecies paratuberculosis (MAP), is a chronic granulomatous enteritis with significant implications for ruminant health, economic productivity, and potential zoonotic risk. This study investigated the expression of biomarkers of oxidative stress and apoptosis in goats naturally infected with MAP, focusing on three biological matrices: serum, intestinal mucosa, and mesenteric lymph nodes. Twenty MAP-positive goats and ten healthy controls were included. Serum and tissue levels of malondialdehyde (MDA), glutathione S-transferase (GST), glutathione peroxidase (GPX), superoxide dismutase (SOD), glutathione reductase (GSR), and caspase-3 were quantitatively assessed using ELISA tests. Gross and histopathological analyses confirmed MAP infection. Infected animals showed significantly elevated serum levels of MDA and caspase-3 (p < 0.001), along with decreased antioxidant enzyme activities (GSR, GST, GPX, SOD). Tissue analysis revealed increased MDA and caspase-3 levels, particularly in the intestinal mucosa compared to mesenteric lymph nodes, suggesting localized oxidative damage and apoptosis. Conversely, antioxidant enzyme activity was higher in mesenteric lymph nodes, indicating a compensatory response and a pronounced involvement of the intestinal tract. These findings demonstrate that MAP infection induces marked oxidative stress and apoptotic processes, especially in the intestinal mucosa. The imbalance between pro-oxidant and antioxidant systems may play a key role in the pathogenesis and chronic progression of the disease. Caspase-3 and MDA, in particular, have been identified as promising diagnostic or prognostic biomarkers for MAP infection. This study highlights the importance of developing improved diagnostic tools and therapeutic strategies targeting oxidative stress pathways in paratuberculosis. Full article

SPS is characterized by progressive spasmodic muscular rigidity. SPS is thought to be an autoimmune disease with a prominent feature of antibodies against glutamic acid decarboxylase (GAD). GAD is responsible for the enzymatic conversion of glutamic acid (glutamate) into the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Reduced GABA activity leads to increased excitability in the central nervous system, resulting in muscle rigidity and spasms characteristic of SPS. While SPS is rare, anti-GAD antibodies seen in SPS are also seen in the much more common autoimmune disease, type 1 diabetes (T1D). There is evolving research showing that the anti-GAD antibodies of T1D are produced in response to the presence of mycobacterial heat shock protein 65 (mHSP65), and the mHSP65 is produced in response to an occult infection by a bacterium, Mycobacterium avium subspecies Paratuberculosis (MAP). Humans are broadly exposed to MAP in food, water, and air. There are linear and conformational similarities between the epitopes of GAD and mHSP65. This article proposes that MAP is also an infectious trigger for SPS. Dehydroepiandrosterone (DHEA) is a principal component of the steroid metabolome; it plateaus in young adults and then steadily declines. Bromo-epi-androsterone (BEA) is a potent synthetic analog of DHEA; unlike DHEA, it is non-androgenic, non-anabolic, and an effective modulator of immune dysregulation. BEA is also an anti-infective agent and has been shown to benefit mycobacterial infections, including tuberculosis and leprosy. With the immune stabilizing capacity of BEA as well as its anti-mycobacterial properties, there is reason to believe that a randomized clinical trial with BEA may be beneficial for SPS. Full article

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that, over millions of years, became integrated into the human genome. While normally inactive, environmental stimuli such as infections have contributed to the transcriptional reactivation of HERV-promoting pathological conditions, including the development of autoimmunity, neurodegenerative disease and cancer. What infections trigger HERV activation? Mycobacterium avium subspecies paratuberculosis (MAP) is a pluripotent driver of human disease. Aside from granulomatous diseases, Crohn’s disease, sarcoidosis and Blau syndrome, MAP is associated with autoimmune disease: type one diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA) and autoimmune thyroiditis. MAP is also associated with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Autoimmune diabetes, MS and RA are the diseases with the strongest MAP/HERV association. There are several other diseases associated with HERV activation, including diseases whose epidemiology and/or pathology would prompt speculation for a causal role of MAP. These include non-solar uveal melanoma, colon cancer, glioblastoma and amyotrophic lateral sclerosis (ALS). This article further points to MAP infection as a contributor to autoimmunity, neurodegenerative disease and cancer via the un-silencing of HERV. We examine the link between the ever-increasing number of MAP-associated diseases and the MAP/HERV intersection with these diverse medical conditions, and propose treatment opportunities based upon this association. Full article

Paratuberculosis (PTB), caused by Mycobacterium avium subspecies paratuberculosis (MAP), is a chronic disease with economic impact on ruminant farming worldwide. The Canary Islands count with the fourth largest goat population in Spain and are “officially free” of bovine tuberculosis. Twelve farms were included with 2774 serum samples tested by an enzyme-linked immunosorbent assay (ELISA) for detection of anti-MAP antibodies in two sessions. In the first session, an overall apparent prevalence of 18.4% (2.5% up to 61.1%) was obtained. Farms with prevalences (0–10%], (10–20%] and >20% were identified, with differences in seroconversion in the same prevalence group between farms and age ranges. Non-vaccinated (nV) and vaccinated (V) animals were included in the second sampling session. Higher levels of antibodies were detected in V animals older than 12 months, with considerable variations between age ranges and farms. Our results describe the current PTB status of the Canary Islands’ goat farming. Furthermore, new insights on the effect of the farm prevalence on seroconversion in V animals are provided, although further studies are needed to evaluate the multiple factors affecting the immune response to anti-MAP vaccination. Full article

Proliferative enteropathy is an enteric disease caused by the bacterium Lawsonia intracellularis, which affects several species of domestic and wild animals. The mechanisms underlying the mechanisms employed by L. intracellularis to cause host cell proliferation are poorly understood, mostly because this bacterium is extremely difficult to isolate and propagate in vitro. Comparative genomics methods for searching for genes orthologous to genes known to be associated with pathogenesis allow identification of genes potentially involved in pathogenesis by the pathogen of interest. The goal of this study was to carry out in silico research on L. intracellularis genes orthologous to genes required for intracellular invasion and survival present in other pathogenic bacteria, particularly Brucella abortus, B. melitensis, B. suis, Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium avium subspecies paratuberculosis, Salmonella enterica, Yersinia pestis, Y. enterocolitica, and Y. pseudotuberculosis. A total of 127 genes associated with invasion and intracellular survival from five known intracellular bacteria were mapped against the predicted proteomes of all L. intracellularis strains publicly available on GenBank, using the OrthoFinder program. A total of 45 L. intracellularis genes were orthologous to genes associated with pathogenesis of other intracellular bacteria. Genes putatively associated with signal the transduction of chemotaxis and cell motility were identified. Genes related to DNA binding and repair were also identified, with some of them supporting a possible association of bacteria with macrophages or inducing pro-inflammatory responses. The homology-based identification of these genes suggests their potential involvement in the virulence and pathogenicity of L. intracellularis, opening avenues for future research and insights into the molecular mechanisms of Lawsonia-elicited proliferative enteropathy. Full article

This study, conducted between 4 October 2013, and 30 November 2018, tested the hypothesis that triple antimicrobial therapy, targeting Mycobacterium avium subspecies paratuberculosis (MAP), long considered a putative cause, would favorably affect Crohn’s disease. A double-blind multicenter study of adults with active Crohn’s disease, (i.e., Crohn’s Disease Activity Index [CDAI] 220–450 plus C-reactive protein ≥ 1.0 mg/dL, fecal calprotectin (FCP) >162.9 µg/g stool, or recent endoscopic or radiographic confirmation of active disease) receiving concomitant standard-of-care Crohn’s disease treatment (Clinicaltrials.gov: NCT01951326) were stratified by anti-tumor necrosis factor use and randomized (1:1) to anti-MAP RHB-104 (clarithromycin 95 mg, rifabutin 45 mg, and clofazimine 10 mg per capsule) (n = 166), resulting in clarithromycin 950 mg/day, rifabutin 450 mg/day, and clofazimine 100 mg/day, or placebo (n = 165) for up to 52 weeks. A greater proportion of RHB-104 versus placebo-treated patients met the primary endpoint—remission (i.e., CDAI < 150)—at week 26 (36.7% [61/166] vs. 22.4% [37/165], respectively; 95% CI for difference: 4.6, 24.0, p = 0.0048; chi-square test). Clinical response (reduction of CDAI by ≥100 points from baseline) at week 26 (first secondary endpoint) was also higher among the patients treated with RHB-104 (73/166 [44.0%]) compared with placebo (50/165 [30.3%]; 95% CI for difference: 3.4, 24.0, p = 0.0116), and it remained higher at week 52 among the patients treated with RHB-104 (59/166 [35.5%] vs. (35/165 [21.2%] for placebo; 95% CI for difference: 4.7, 23.9, p = 0.0042). A statistically significantly greater decline in FCP (another prospective efficacy endpoint) was also observed in RHB-104-treated patients, compared with placebo, at weeks 12, 26, and 52. The rates of serious adverse events were similar between groups (RHB-104: 18.7%; placebo: 18.8%). No patient died during the study. Antimicrobial therapy directed against MAP resulted in significantly greater improvement in clinical and laboratory (FCP) measures of active Crohn’s disease. Full article

Neutrophils are believed to play a role in the initial stages of paratuberculosis, and it has recently been demonstrated that vaccination can modulate their function via priming or through epigenetic and metabolic reprogramming (training). Modulation of the neutrophil response against Mycobacterium avium subspecies paratuberculosis (Map) through vaccination has been demonstrated in a rabbit model but not in ruminants. Therefore, in the present work, the effect of vaccination on the response of caprine neutrophils against Map was studied. Neutrophils were isolated from non-vaccinated (n = 7) and Gudair^®-vaccinated goat kids (n = 7), before vaccination and 30 days post-vaccination. Then, several neutrophil functions were quantified ex vivo: cell-free and anchored neutrophil extracellular trap (NET) release, phagocytosis, and the differential expression of several cytokines and TLR2. The induction of cell-free NETosis and TLR2 expression by Map is reported for the first time. However, vaccination showed no significant effect on any of the functions studied. This suggests that the protection conferred by Gudair^® vaccination is based on mechanisms that are independent of the neutrophil function modulation. Further research into the impact of alternative vaccination strategies or the paratuberculosis infection stage on ruminant neutrophil function could provide valuable insights into its role in paratuberculosis. Full article