Leprosy is a poverty-associated infectious disease in humans caused by Mycobacterium leprae or M. lepromatosis, often resulting in skin and peripheral nerve damage, which remains a significant public health concern in isolated areas of low- and middle-income countries. Previous studies reported leprosy in red squirrels in the British Isles, despite the fact that autochthonous human cases have been absent for centuries in this region. To investigate the extent of M. leprae and M. lepromatosis presence in wild red squirrels in the northern UK, we analyzed 220 blood/body cavity fluid samples from opportunistically sampled red squirrels (2004-2023) for specific antibodies against phenolic glycolipid-I, a cell wall component specific for these leprosy bacilli. Additionally, we assessed bacillus-derived DNA by real-time PCR (qPCR) in 250 pinnae from the same cohort. M. lepromatosis and M. leprae DNA were detected by qPCR in 20.4% and 0.8% of the squirrels, respectively. No cases of co-detection were observed. Detectable levels of anti-PGL-I antibodies by UCP-LFA were observed in 52.9% of animals with the presence of M. lepromatosis determined by qPCR, and overall in 15.5% of all animals. In total, 22.6% (n = 296) of this UK cohort had at least some exposure to leprosy bacilli. Our study shows that leprosy bacilli persist in red squirrels in the northern UK, emphasizing the necessity for ongoing molecular and serological monitoring to study leprosy ecology in red squirrels, gain insight into potential zoonotic transmission, and to determine whether the disease has a conservation impact on this endangered species.

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UNASSIGNED: The Lucio phenomenon (LP) is a characteristic reaction pattern seen in patients with diffuse lepromatous leprosy (DLL). Dual infection with Mycobacterium leprae and Mycobacterium lepromatosis in DLL has been confirmed from other endemic countries but not previously documented from India. Conventionally, LP is treated with a high dose of systemic glucocorticoid (GC) and anti-leprosy treatment (ALT). Here we report a case of leprosy lymphadenitis at initial presentation in a patient with LP and DLL due to dual infection with M. leprae and M. lepromatosis who responded favourably to tofacitinib as adjuvant to ALT and systemic GC therapy.
UNASSIGNED: A 20- to 30-year-old man presented with swelling over the bilateral inguinal region, pus-filled skin lesions with multiple ulcers, fever and joint pain. Post-hospitalization investigations showed the presence of anaemia, leukocytosis, and elevated acute and chronic inflammatory markers. Skin and lymph node biopsies were suggestive of LP and leprosy lymphadenitis. The presence of M. leprae and M. lepromatosis was confirmed by PCR followed by DNA sequencing of PCR amplicons from tissue. Despite anti-leprosy treatment, oral GC and thalidomide therapy, the patient continued to develop new lesions. One month after the commencement of adjuvant tofacitinib, the patient showed excellent clinical improvement with healing of all existing lesions and cessation of new LP lesions.
UNASSIGNED: Our case confirms the presence of dual infection with M. leprae and lepromatosis in India. Lymph node involvement as an initial presentation of DLL should be considered in endemic areas. Tofacitinib may be a promising new adjuvant therapy for recalcitrant lepra reactions.

In 2008, bacilli from 2 Hansen disease (leprosy) cases were identified as a new species, Mycobacterium lepromatosis. We conducted a systematic review of studies investigating M. lepromatosis as a cause of HD. Twenty-one case reports described 27 patients with PCR-confirmed M. lepromatosis infection (6 dual M. leprae/M. lepromatosis): 10 case-patients in the United States (7 originally from Mexico), 6 in Mexico, 3 in the Dominican Republic, 2 each in Singapore and Myanmar, and 1 each in Indonesia, Paraguay, Cuba, and Canada. Twelve specimen surveys reported 1,098 PCR-positive findings from 1,428 specimens, including M. lepromatosis in 44.9% (133/296) from Mexico, 3.8% (5/133) in Colombia, 12.5% (10/80) in Brazil, and 0.9% (2/224) from the Asia-Pacific region. Biases toward investigating M. lepromatosis as an agent in cases of diffuse lepromatous leprosy or from Mesoamerica precluded conclusions about clinicopathologic manifestations and geographic distribution. Current multidrug treatments seem effective for this infection.

Leprosy is a neglected tropical disease (NTD) that continues to burden low- and middle-income countries (LMICs), despite being eliminated as a public health concern by the World Health Organization (WHO) in 2000. The causative agents, Mycobacterium leprae and Mycobacterium lepromatosis, affect nearly 200,000 individuals globally each year, with over 19,000 new cases detected in the Americas in 2020 alone. Canada has experienced an increasing incidence of leprosy, due to rising levels of travel and migration from endemic areas, reaching over 37,000 individuals with leprosy by the end of 2020. Patients experience a spectrum of signs and symptoms including hypopigmented cutaneous macules alongside peripheral neuropathy including peripheral neuropathic pain (PNP) and disabling sensory neuropathies. Despite the development of effective and curative therapeutics via multidrug therapy (MDT), many barriers to treatment adherence and effective immunological control of the pathogen challenge the care of patients with leprosy. Socioeconomic barriers, such as disability-related social stigma and often undiagnosed nutritional deficiencies, have resulted in heightened disease severity. PNP therapeutics are associated with significant side effects and remain ineffective as the majority of individuals will not experience a greater than 30% reduction of symptoms. Nutrient supplementation is known to be instrumental in reducing host oxidative stress, strengthening the immune system and mitigating comorbidities. Likewise, dietary lifestyle interventions known to be physiologically beneficial have recently emerged as powerful tools conferring neuroprotective effects, potentially mitigating PNP severity. However, a significant knowledge gap concerning the effect of adequate nutrition on host immunological control of leprosy and PNP severity exists. Further evaluation of this relationship will provide key insight into the pathogenesis of leprosy, strengthening the current body of literature.

Leprosy is caused by Mycobacterium leprae and Mycobacterium lepromatosis. We report construction and analyses of the complete genome sequence of M. lepromatosis FJ924. The genome contained 3,271,694 nucleotides to encode 1,789 functional genes and 1,564 pseudogenes. It shared 1,420 genes and 885 pseudogenes (71.4%) with M. leprae but differed in 1,281 genes and pseudogenes (28.6%). In phylogeny, the leprosy bacilli started from a most recent common ancestor (MRCA) that diverged ~30 million years ago (Mya) from environmental organism Mycobacterium haemophilum. The MRCA then underwent reductive evolution with pseudogenization, gene loss, and chromosomal rearrangements. Analysis of the shared pseudogenes estimated the pseudogenization event ~14 Mya, shortly before species bifurcation. Afterwards, genomic changes occurred to lesser extent in each species. Like M. leprae, four major types of highly repetitive sequences were detected in M. lepromatosis, contributing to chromosomal rearrangements within and after MRCA. Variations in genes and copy numbers were noted, such as three copies of the gene encoding bifunctional diguanylate cyclase/phosphodiesterase in M. lepromatosis, but single copy in M. leprae; 6 genes encoding the TetR family transcriptional regulators in M. lepromatosis, but 11 such genes in M. leprae; presence of hemW gene in M. lepromatosis, but absence in M. leprae; and others. These variations likely aid unique pathogenesis, such as diffuse lepromatous leprosy associated with M. lepromatosis, while the shared genomic features should explain the common pathogenesis of dermatitis and neuritis in leprosy. Together, these findings and the genomic data of M. lepromatosis may facilitate future research and care for leprosy. IMPORTANCE Leprosy is a dreaded infection that still affects millions of people worldwide. Mycobacterium lepromatosis is a recently recognized cause in addition to the well-known Mycobacterium leprae. M. lepromatosis is likely specific for diffuse lepromatous leprosy, a severe form of the infection and endemic in Mexico. This study constructed and annotated the complete genome sequence of M. lepromatosis FJ924 and performed comparative genomic analyses with related mycobacteria. The results afford new and refined insights into the genome size, gene repertoire, pseudogenes, phylogenomic relationship, genome organization and plasticity, process and timing of reductive evolution, and genetic and proteomic basis for pathogenesis. The availability of the complete M. lepromatosis genome may prove to be useful for future research and care for the infection.

Mycobacterium lepromatosis was identified as a new species and second causal agent of Hansen\'s disease (HD, or leprosy) in 2008, 150years after the disease was first attributed to Mycobacterium leprae. M. lepromatosis has been implicated in a small number of HD cases, and clinical aspects of HD caused by M. lepromatosis are poorly characterized. HD is a recognized zoonosis through transmission of M. leprae from armadillos, but the role of M. lepromatosis as a zoonotic agent of HD is unknown. M. lepromatosis was initially associated with diffuse lepromatous leprosy, but subsequent case reports and surveys have linked it to other forms of HD. HD caused by M. lepromatosis has been reported from three endemic countries: Brazil, Myanmar, and Philippines, and three non-endemic countries: Mexico, Malaysia, and United States. Contact with armadillos in Mexico was mentioned in 2/21 M. lepromatosis HD case reports since 2008. M. lepromatosis in animals has been investigated only in non-endemic countries, in squirrels and chipmunks in Europe, white-throated woodrats in Mexico, and armadillos in the United States. To date, there have only been a small number of positive findings in Eurasian red squirrels in Britain and Ireland. A single study of environmental samples found no M. lepromatosis in soil from a Scottish red squirrel habitat. Future studies must focus on endemic countries to determine the true proportion of HD cases caused by M. lepromatosis, and whether viable M. lepromatosis occurs in non-human sources.

The genome of a newly identified leprosy causing bacillus Mycobacterium lepromatosis was sequenced in 2015 wherein a gene MLPM_5000 was detected whose corresponding sequences are missing in its close relative Mycobacterium leprae, the well-known causal agent of leprosy. Thus MLPM_5000 is considered to be a specific genomic locus for differentiating M. lepromatosis from M. leprae. The locus was annotated as HemN (Coproporphyrinogen III oxidase) based on the available annotations in other mycobacterial species. However, we noticed that the MLPM_5000 and its orthologues in different mycobacterial species show a much higher degree of similarity with Escherichia coli HemW (378 aa) in comparison to the E. coli HemN (457 aa). Additionally, the fourth cysteine of the characteristic CX3CX2CXC motif of the E. coli HemN is replaced by a phenylalanine in the M. lepromatosis MLPM_5000 and its mycobacterial orthologues, which is a hallmark of heme chaperone protein HemW in E. coli and other species. Phylogenetic analysis of MLPM_5000 and its mycobacterial orthologues also showed that these proteins form a divergent phylogenetic clade with the HemW proteins of other species such as Escherichia coli and Lactococcus lactis. Further, Molecular Dynamics simulation studies also predicted that the residues of conserved HNXXYW motif of the MLPM_5000 may have a role in binding to heme part of the host hemoglobin, thereby suggesting it to be a HemW instead of HemN. Altogether, this work shows that MLPM_5000 and its mycobacterial orthologues are highly unlikely to be HemN. Therefore, the current annotations of mycobacterial HemN sequences should be corrected to heme chaperone \'HemW\' in various protein databases. The study not only corrects the mis-annotation but also provides a new perspective in the context of evolutionary history of M. leprae and M. lepromatosis such as lack of HemW in M. leprae may explain some of the variations in the virulence between the two pathogens.

UNASSIGNED: The causative agents of leprosy are the well-known Mycobacterium leprae and the newly discovered Mycobacterium lepromatosis. This agent was found in 2008, and it was found to be the cause of diffuse lepromatous leprosy in two Mexican patients.
UNASSIGNED: The objective of this work was to determine if M. leprae and M. lepromatosis were present in formalin-fixed and paraffin-embedded skin samples from cases from different regions in Mexico.
UNASSIGNED: A total of 41 skin samples were obtained from 11 states of Mexico. All patients\' samples were diagnosed by clinical and histopathological analyses. Total DNA was isolated using a Qiagen-DNeasy blood and tissue kit and molecular identification was achieved by two semi-nested polymerase chain reactions.
UNASSIGNED: The 41 patient included 33 samples from men and 8 samples from women; 29 samples were polymerase chain reaction (PCR)-positive to Mycobacterium and 12 samples were PCR-negative. From those 29 samples, 13 were PCR-positive to M. leprae, 8 to M. lepromatosis and 8 were positive to both species. The histopathological diagnosis included; Nodular lepromatous leprosy (NLL); Diffuse lepromatous leprosy (DLL); and Borderline leprosy (BL). The 29 PCR-positive samples were classified as follow: 14 NLL, 4 DLL, and 11 BL. In the 12 samples negative to Mycobacterium, 7 showed the NLL, 2 DLL and 3 BL.
UNASSIGNED: These findings add evidence to the M. leprae and M. lepromatous distribution, clinical forms and participation of dual infections in Mexico.

BACKGROUND: Mycobacterium leprae and Mycobacterium lepromatosis are gram-positive bacterial pathogens and the causative agents of leprosy in humans across the world. The elimination of leprosy cannot be achieved by multidrug therapy alone, and highlights the need for new tools and drugs to prevent the emergence of new resistant strains.
METHODS: In this study, our contribution includes the prediction of vaccine targets and new putative drugs against leprosy, using reverse vaccinology and subtractive genomics. Six strains of Mycobacterium leprae and Mycobacterium lepromatosis (4 and 2 strains, respectively) were used for comparison taking Mycobacterium leprae strain TN as the reference genome. Briefly, we used a combined reverse vaccinology and subtractive genomics approach.
RESULTS: As a result, we identified 12 common putative antigenic proteins as vaccine targets and three common drug targets against Mycobacterium leprae and Mycobacterium lepromatosis. Furthermore, the docking analysis using 28 natural compounds with three drug targets was done.
CONCLUSIONS: The bis-naphthoquinone compound Diospyrin (CID 308140) obtained from indigenous plant Diospyros spp. showed the most favored binding affinity against predicted drug targets, which can be a candidate therapeutic target in the future against leprosy.