However, there is an ongoing risk that the latent infection may escalate to active disease. The risk is increased by other illnesses such as HIV or medications which compromise the immune system. To protect against this, the United States employs a strategy of preventive therapy or treatment of latent TB infection.
Masks are required for all patients, visitors, employees and staff. Thank you. Tuberculosis: Types. Page last reviewed: 12 November Next review due: 12 November Latent or active TB In most healthy people, the immune system is able to destroy the bacteria that cause TB.
Who's most at risk? Actually, a considerable proportion of infected individuals are competent to clear the pathogen and develop sterile granulomas. On the other side, in order to overcome host immune responses and hypoxic environment, M.
Both innate e. For example, when the host immunity is compromised, M. Thus, maintaining solid granulomas in infected individuals is a hallmark of the balanced confrontation between M. Immune homeostasis in granulomas can be regulated by AMs with two polarized types, known as classically activated macrophages M1 macrophages and alternatively activated macrophages M2 macrophages Hussell and Bell, M1 macrophages are crucial for suppressing TB progression, but uncontrollable inflammation may induce severe tissue damage Hussell and Bell, , which can be counterbalanced by M2 macrophage- and Th2 cell-mediated immunosuppressive regulation.
Remarkably, it seems that during TB development, the host is biases to Th2-type immunity, which is deemed to be beneficial for the intracellular survival of M.
Figure 1. Unbalanced immune system in TB patients results in the development of diverse diseases. After inhalation of M. When the host becomes immunocompromised, M. Non-caseating granulomas may continously exist after bacteria elimination and present as sarcoidosis because of excessive host inflammatory immune responses 2.
The infected cells, M. The gut microbiota is also involved in the interplay between M. Surprisingly, recent studies suggest that mycobacteria are able to invade various non-canonical immune cells, including epithelial cells, endothelial cells, fibroblasts, adipocytes, and neuronal cells Randall et al.
This ability of M. A key prerequisite for intracellular colonization of mycobacteria is their ability to adhere and enter host cells. To date, an array of host PRRs has been identified that mediate phagocytosis of M. Those PRRs include mannose receptors, complement receptors, Fc receptors, and C-type lectin receptors, including dendritic cell-specific intercellular adhesion moleculegrabbing non-integrin DC-SIGN and macrophage inducible C-type lectin Mincle Ernst, ; Ishikawa et al.
In contrast, few molecular components from M. Loss of HBHA decreases mycobacterial adhesion and the invasion of epithelial cells but not macrophages Pethe et al. Recently, M. Mammalian cell entry Mce family proteins are another group of bacterial surface-exposed molecules associated with host cell entrance.
The mce1 gene recombined into Escherichia coli confers the bacteria with the capacity to invade epithelial cells Arruda et al. Lately, our lab has confirmed that Mce3C can also facilitate the internalization of M.
The host exerts both innate and adaptive immune functions to protect against M. Initially, the innate immune cells rapidly respond by direct recognition of conserved pathogen-associated molecular patterns PAMPs like lipoproteins, glycolipids, and carbohydrates on the M. Subsequently, a variety of immune mechanisms, such as phagocytosis, autophagy, apoptosis, and inflammasome assembly, are evoked to efficiently control M. In addition, recent studies imply that B cell-mediated humoral immunity can also manipulate the inflammatory responses in TB granulomas to control local infection, despite a minor effect on overall pathology or disease progression being observed Maglione et al.
Notably, host adaptive immunity to M. This delayed response has not yet been entirely explained, though one possibility is that M. Host innate immunity against M. Upon infection by M. The ESX-1 system is the most studied secretion system in mycobacteria and has been well-characterized for its vital effects on host immune triggering e. Notably, ESX-1 is not the exclusive system that determines mycobacterial pathogenesis, because some effector proteins expressed in BCG, which spontaneously lacks the esx-1 locus, are still secreted and effective in facilitating bacterial survival in host cells.
For example, we previously revealed that M. Interestingly, host innate immune cells also apply restriction factors to antagonize the function of pathogen effector proteins. For example, many tripartite motif TRIM family proteins have been demonstrated to serve as host restriction factors via regulating innate immunity and counteracting the effects of some viral effector proteins Hatakeyama, In the case of M.
Thus, there exists an evolutionary dynamics of interactions between host restriction factors and pathogen antagonists during mycobacterial infection. As the portal of bacterial entry, the lung is the most commonly affected organ during M. The respiratory tract and the bronchoalveolar spaces represent a unique immunological compartment where diverse tissue-specific cells shape the first-line immune response to inhaled M.
These interactions alter the pulmonary microenvironment, which may remodel the airways and influence the development and outcomes of various pulmonary diseases. COPD is characterized by airflow limitation associated with an enhanced chronic inflammatory response, both in the airway and the lung, to noxious particles or gases, such as the substances produced by tobacco smoking.
Recently, epidemiological studies have provided a strong link between past history of TB and later development of chronic airflow obstruction Amaral et al. Growing evidence argues that pulmonary TB can lead to remodeling of the lung architecture, which can be manifested as extensive fibrosis, cavitation, traction bronchiectasis, bronchostenosis, or parenchymal lung destruction Dheda et al.
Chronic airflow obstruction is also suggested to be a sequel to active TB because of the development of bronchiectasis in patients with COPD Chakrabarti et al. In addition, human pneumonia, as another pulmonary disease that commonly occurs in TB patients especially adolescents who have strong immunological responses , can also increase morbidity and mortality rates related to acute exacerbations of COPD Modesto dos Santos et al. Both TB and lung cancer represent global threats claiming millions of lives worldwide.
Clinical data show that TB and lung cancer may co-exist in some cases, and the history of TB infection is reported as a risk factor for lung cancer development Brenner et al. As has been described, M. Chronic inflammatory conditions are thought to create the appropriate microenvironment for cancer development by a number of mechanisms. Specifically, the higher rate of cell turnover likely increases the risk for genetic errors to trigger carcinogenesis.
Additionally, the enhanced cell-mediated immune responses caused by mycobacterial infection could result in the extension of pulmonary fibrosis, which could probably contribute to the development of lung scar carcinoma Ardies, Intriguingly, recent research from our laboratory have demonstrated that M.
Animal experimental evidence also revealed that chronic TB infection could lead to cell dysplasia and squamous cell carcinoma specifically in the lung Nalbandian et al. Because the causal relationship between TB and lung cancer remains inconclusive and similarities between those two lung diseases might mislead diagnosis, further investigations are needed to fully understand the underlying mechanisms linking M.
The development of AIDs is determined by a combination of genetic, hormonal, and environmental factors, as well as the immunological status of the individual. Mycobacterial infection is implicated as an environmental trigger to initiate AIDs. For example, intravesical administration of BCG for bladder cancer triggers systemic autoimmunity Sampaio et al. Clinical data also support the notion that M. There are three possible mechanisms accounting for the potential development of AIDs following TB infection.
The first mechanism is molecular mimicry by which the mycobacterial components incorporate an epitope that is structurally similar to that of a self-antigen Blank et al.
For example, M. Third, TLR-mediated signaling activation caused by M. Next, we discuss two TB-associated AIDs, sarcoidosis and SLE, with an aim to better elucidate the intricate relationship between mycobacterial infection and autoimmunity. Sarcoidosis, an AID with no definite proof of an infectious etiology, is characterized by the presence of non-caseating granulomas with accumulated epithelioid cells in various organs. A previous study reports that mycobacterial DNA can be identified in sarcoidosis lesions Song et al.
Furthermore, mycobacterial HSPs are detected with high expression in sarcoidosis tissue as well, suggesting that those proteins may also participate in the etiopathogenesis of sarcoidosis. Remarkably, multiple effector proteins secreted by M. For example, bronchoalveolar lavage cells from sarcoidosis patients exhibit increased cytokine responses to the kDa lipoprotein of M. Due to the similar clinical and histopathological features of sarcoidosis and TB, some investigators argue that they may be the same disease with varying presentations Agrawal et al.
However, noting that anti-TB treatment seemly has little effect on sarcoidosis patients Dubaniewicz et al. SLE is a systemic disease of unknown etiology that is characterized by autoantibodies against self-antigens, resulting in various inflammation-mediated systemic symptoms. Infections, renal failure, and cardiovascular diseases account for the majority of deaths seen in SLE patients Ward et al. Several studies suggest that patients with SLE are at increased risk of reactivation and dissemination of TB due to multiple immune abnormalities and immunosuppressive therapy Yun et al.
Meanwhile, there is also growing evidence that supports the pivotal role of mycobacterial infection in induction and exacerbation of SLE Ghosh et al. In this context, several studies report the development of SLE after TB infection and the presence of autoantibodies, such as antinuclear antibodies ANA and rheumatoid factor RF , in the sera of patients with active TB are attributed to cross-reactivity between mycobacterial and host self-antigens Amital-Teplizki et al.
Taken together, it can be postulated that M. The metabolic system plays a central role in maintaining the stable nutritional status of the host, which is crucial for anti-TB immunity Paranandi and Wanke, The effect of host metabolism on M. Sensing pathogenic threats by innate immune cells triggers the responses of immune signaling networks, allowing a bulk of genes to initiate transcription and expression.
This is followed by the release of inflammatory cytokines and chemokines and, subsequently, the expansion and differentiation of adaptive immune cells. Undoubtedly, sustaining the efficiency of these immune processes is faced with the urgent need for energy, resulting in a metabolic switch from oxidative phosphorylation to aerobic glycolysis also known as the Warburg effect Warburg et al.
Despite oxygen availability, the activated immune cells predominantly metabolize glucose into the pentose phosphate pathway PPP and prefer to excrete pyruvate generated by glycolysis as lactate rather than shuttle it into the tricarboxylic acid TCA cycle Pearce and Pearce, Furthermore, adaptive immune cells can also flexibly utilize other metabolites, such as glutamine via glutaminolysis, to supply the TCA cycle and fuel mitochondrial oxidative phosphorylation OXPHOS for their proliferation Wang et al.
It should also be pointed out that metabolic reprogramming commonly occurs in both innate and adaptive immune cells including M1 macrophages, neutrophils, DCs, NK cells, T, and B cells after being activated Gaber et al. A well-established paradigm is the metabolic disposition between M1 and M2 macrophages. Aside from the prominent activity of glycolysis and glutaminolysis, inducing M1 macrophages with TLR4 agonist also leads to a boost in the eicosanoid synthesis pathway, a metabolic process of polyunsaturated fatty acids that produces several inflammation-related metabolites like prostaglandins and leukotrienes Norris et al.
It is increasingly appreciated that host metabolic disorders could benefit TB development, and M. Next, we summarize current knowledge on the reciprocal regulation of M.
In addition, cohort studies and clinical evidence suggest that people with DM have a nearly three-fold risk of active TB as compared to non-DM cases and may develop more severe symptoms in the lung Jeon and Murray, ; Leung et al.
For example, several studies demonstrate that either spontaneous or chemically induced T2DM animal models including mice, rats, and guinea pigs infected with M. Another intriguing finding is that a strengthened host proinflammatory response and intensified mycobacterial proliferation only occur in chronic but not acute DM-TB infection models Martens et al.
Consistently, TB progression in DM models is not obviously different from that in normal controls until the late stage of infection Podell et al. Taken together, these studies suggest that the impaired anti-TB immunity in DM patients may result from a long-term impact of disordered metabolic status that results from both DM and TB. However, the detailed mechanisms regarding how the courses of TB and DM influence each other through regulation of the metabolic system still remain largely unknown.
Obesity is answerable to the increasing global DM prevalence Popkin, Interestingly, several studies suggest that overweight and obese individuals are conferred with protection against TB risk Leung et al. These results seem to be consistent with the findings that malnutrition exacerbates the morbidity and mortality of TB Paranandi and Wanke, However, it is difficult to conclude that gaining weight is good for host anti-TB immunity because multiple confounding factors could be involved in these studies e.
However, evidence based on animal experiments implies an immunomodulatory function of adipose tissue during M. Leptin, an adipokine mainly secreted by adipocytes, is a pleiotropic factor involved in the metabolic, neuroendocrine, and immune systems Abella et al. It has been shown that Leptin-deficient animal models exhibit a much weaker immune defense against mycobacterial infection Wieland et al. Furthermore, a lipidomics study in high-fat diet-induced obese mice revealed a distinct change of eicosanoid metabolites Wang W.
Nevertheless, further studies are warranted to better elucidate the impacts of obesity with altered metabolic status, such as elevated levels of fatty acids and cholesterol, on M. Epidemic data imply a presumptive connection between TB and atherosclerotic disease Chung et al.
Consistently, mycobacterial HSP65 and the human homolog HSP60 are detected at heightened serum levels in atherosclerotic patients Xu et al.
In addition, high-cholesterol diet-induced atherosclerotic animals immunized with HSP65 display an accelerated progression of disease, while oral tolerization with HSP65 can block the advanced formation of atherosclerotic plaques Zhang et al. Atheroma has long been considered as a chronic infectious disease associated with multiple pathogens, including M. One possible explanation for this phenomenon could be that pathogen infection evoking a host Th1-type immune response may also intensify the inflammation at an early stage of plaque formation Frostegard et al.
Interestingly, the immunological progression of atherosclerosis shares similar patterns with the formation of TB granulomas. Atherosclerosis is initiated by aberrant retention of oxidized low-density lipoprotein oxLDL in the arterial intima, which recruits inflammatory cells, including lymphocytes, monocytes, and macrophages, to the subendothelial space Chinetti-Gbaguidi et al.
Subsequently, the macrophages scavenge the lipoprotein particles by storing them as lipid droplets LDs in their cytoplasm and turn into foam cells. Increased deposition of oxLDL and inflammation result in apoptosis of these macrophages, leading to the formation of a necrotic core in the plaque, followed by further inflammation and thrombosis Chinetti-Gbaguidi et al. Likewise, there are also foamy macrophages FMs distributed in the interface region around the necrotic center of TB granulomas Peyron et al.
These FMs containing quiescent M. During chronic atherosclerosis, senescent FMs are deleterious throughout disease development, but due to the Th1-dominant response in the lesions, such FMs cannot be promptly cleared by M2 macrophages via efferocytosis Viola and Soehnlein, ; Childs et al.
Thus, it is intriguing to investigate the role of M. Interestingly, one study has demonstrated a potential anti-atherosclerotic effect of BCG van Dam et al. Vitamins are essential micronutrients for maintaining individual health.
One of the most studied vitamins is vitamin D, which demonstrates potential benefits in the treatment of multiple diseases, including TB Feldman et al. Accumulating studies provide a mechanistic understanding of the effects of vitamin D signaling on the regulation of the host immune defense against M. First, the activation of TLRs in mycobacteria-infected monocytes is indispensable to boost the synthesis pathway of 1,dihydroxy-vitamin D 3 1,25 OH 2 D 3 , the active form of provitamin D 3 , which leads to the production of an antimicrobial peptide to kill the bacilli Liu et al.
Second, 1,25 OH 2 D 3 stimulates autophagy and phagosomal maturation, leading to the repression of mycobacterial growth and HIV-1 replication during co-infection Campbell and Spector, Third, treatment of infected macrophages with vitamin D reduces the formation of lipid drops in the cytoplasm, which may limit the nutrition source for M.
Accumulating data suggest that the level of serum vitamin D is decreased in TB patients but whether this decline is a causal risk factor of TB or a subsequent result of TB infection is undetermined Azam et al.
Though it seems promising, the feasibility of utilizing micronutrients such as vitamins D, C, and B6 with potential anti-TB effects as auxiliary anti-TB treatments still needs further confirmation Dick et al. Increasing evidence shows that the diversity of microbiota, which constitutes the integrated microbiome, can vastly vary in different niches within and among healthy individuals and has a strong influence on immune balance and health conditions.
Here, we mainly focus on the description of the gut and lung microbiomes and the mutual regulation of these local microbial communities and M. The human gut harbors nearly trillion microbial cells and more than bacterial species in each individual Qin et al. The integration of these microbial communities has been proposed as a novel endocrine organ in humans Clarke et al.
By virtue of metabolites delivered from commensal microbes, the host immune system is substantially regulated by gut microbiota. For instance, bacterial short-chain fatty acids are abundantly found in the colonic lumen, among which, n-butyrate has been identified as an inhibitor of histone deacetylases in lamina propria macrophages to diminish cell proinflammatory responses Chang et al.
This hyporesponsiveness may benefit the immune ignorance of indigenous microbes. Another example is that tryptophan Trp metabolites secreted by gastrointestinal microbiota participate in host immunomodulation as revealed by recent work showing that indolealdehyde produced by lactobacilli stimulates IL transcription in innate lymphoid cells ILCs via the Trp metabolic pathway and promotes mucosal resistance against fungus Zelante et al.
Furthermore, a special subset of microbes can also colonize intestinal lymphoid tissues and reside in DCs to directly modulate cytokine production, which then boosts local Th17 and ILCs responses Fung et al.
However, the gastrointestinal TB could be underreported because of limited and insensitive diagnostic approaches Horvath and Whelan, ; Shah and Chida, The invasion of M. A study monitoring the dynamics of gut microbiota in mice before and after aerosol challenge with M. However, whether this disturbance of microbiota is a potential risk factor for developing other diseases remains unknown. Regardless, dysbiosis of the gut microbiota by antibiotic treatment in mice does promote the colonization and dissemination of M.
Intriguingly, an increasing number of studies reveal that Mycobacterium avium subspecies paratuberculosis , another pathogenic mycobacterium, acts as an infectious factor for inflammatory bowel diseases IBDs and has been isolated from the terminal ileum of patients with Crohn's disease Chiodini et al.
The human respiratory microbiome remains a largely unexplored frontier. However, sequencing-based metagenomics and more recently developed microbial culturomics based on mass spectrometry techniques have complementarily provided access to the study of the non-cultivable species Lagier et al. Compared to the human gut, the lung surface is topologically exposed to the outside environment with bidirectional air flow and microbial migration.
Notably, microbes from the upper respiratory tract may immigrate into the lung by microaspiration because the bacterial communities in the oral cavity share similar membership with those in healthy lungs Bassis et al. Any destabilization of the lung environment could lead to variation in the local microbiota.
In particular, the dynamic alternation of the lung microbial structure in patients with chronic lung diseases, such as COPD, asthma, cystic fibrosis, and idiopathic pulmonary fibrosis, has a significant association with disease exacerbations Dickson et al.
Several sputum-based microbiota analyses demonstrate that TB patients exhibit altered community diversity compared to healthy subjects, and a number of distinct foreign bacteria have been identified in the sputum samples from TB patients Cui et al.
In those studies, microbes such as Streptococcus and Pseudomonas are dominant in TB samples, yet there is no clear consensus on the frequency and abundance of the bacterial genera defined in TB patients. Most infections occur in the tropical regions of West and Central Africa.
In Australia, most cases occur in a temperate area around the city of Melbourne. This infection starts as a lump under the skin, a large swollen area, or generalized swelling of the legs, arms, or face. The affected area is painless. The infection progresses, causing open sores on the legs or arms and resulting in widespread destruction of the skin and underlying tissues.
Mycobacterium ulcerans infection is treated with a combination of antibiotics and sometimes surgery. Other types of mycobacteria, such as Mycobacterium fortuitum , can infect wounds, tattoos, and artificial body parts, such as a mechanical heart valve or a breast implant.
Another type of mycobacteria caused severe infections when contaminated water was used to clean out root canals in children. If this treatment is ineffective, people are referred to an experienced specialist. Merck and Co. From developing new therapies that treat and prevent disease to helping people in need, we are committed to improving health and well-being around the world. The Manual was first published in as a service to the community.
Learn more about our commitment to Global Medical Knowledge. This site complies with the HONcode standard for trustworthy health information: verify here. Common Health Topics. Mycobacterium avium complex Infection. Other Nontuberculous Mycobacteria Infections. Skin infections Other infections. Tuberculosis and Related Infections.
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