Background: Mycobacterium tuberculosis, the etiology of pulmonary and extra pulmonary tuberculosis is taunted to have predated the existence of mankind, and science has elucidated its presence in old Egyptian’ mummies, as it continues to evade current antibiotic treatments, wreck the havoc and decimate human populations. Presented here, are the Strengths, Weaknesses, Opportunities and Threats (SWOT) analysis of Mycobacterium tuberculosis, and the first proposal for the application of this innovative concept in the field of Tuberculosis research, to proffer holistic platform, focused knowledge, and strategies at undermining the prowess of the tubercle bacilli and overcoming its scourge. Materials and Methods: A systematic review was carried out to mine data on the strengths, the weaknesses, the opportunities and threats to M. tb, by review of several publications using meaningful theme and specific search phrases on the subject. Results: Strengths of Mycobacterium tuberculosis include: possession of abundant cell wall mycothiol; M. tb is highly contagious and requires low infectious dose (ID50) to establish infection; ability to specifically target and replicate in the host’ macrophages; ability to establish extrapulmonary multiorgan involvement; dual polymorphism i.e. existence in both an actively replicating form as well as or latent state; assumption of variable metabolic states; delayed seeding from the lungs of the replicating bacteria cells to the mediastinal lymph nodes; delayed macrophage apoptosis prior to bacterial growth and ultimate cellular necrosis; ability to shift to glyoxylate pathway during lipid metabolism in lieu of glucose during persistence phase in the host. Weaknesses of M. tuberculosis include: the requirement for growth of a membrane protein called Rv3671c during in vivo replication for survival in the acidic milieu of the macrophages and phagosome; M. tb is a fastidious slow growing bacterium with long generation time; establishment of productive infection in less than 10% of infected subjects; the bacterium is strictly an intracellular aerobic pathogen; and variable bacteria level of adenosine triphosphate. Opportunities harnessed by M. tb include: development and spread of resistant strains owing to inadequate and inappropriate drug treatment; limited efficacy and use of BCG Vaccine; MDR-TB is under-diagnosed in children; pathogenic synergy of coinfection of the Human Immunodeficiency Virus (HIV) and Mycobacterium tuberculosis (MTB); difficulty of TB screening in HIV-infected persons; immune status of the host; immigration; slow response of the cellular immune response to M. tbwhich enables constant endogenous reinfection of the host; anatomical vulnerability of the lungs; aerosols by inspired air is crucial for latent tuberculosis infection. Threats to M. tuberculosis include: the development and use of sensitive combination of microbiological tests as the gold-standard in HIV infected patients; annual TB test; selective isolation of TB patients by reintroduction of sanatoria; prioritizing genomic drug targets; sustenance of the global TB funds; development of potent vaccine; live imaging using computer tomography and positron electron tomography to characterize active TB in lesions; development and application of Infecton for imaging deep seated infections.
Mycobacterium tuberculosis was discovered and described by Robert Koch on 24 March 1882, about 130 years ago, as the causative agent of tuberculosis (TB). The bacterium is an acid fast bacillus with unique cell wall composition. Under Light microscope, the tubercle bacilli typically appear as straight or slightly curved rods. In response to growth conditions and age of the culture, bacilli may vary in size and shape from coccobacilli to long rods. The dimensions of the bacilli have been reported to be 1 - 10 µm in length (usually 3 - 5 µm), and 0.2 - 0.6 µm in diameter. The possibility of morphological variations in tubercle bacilli was suggested by few investigators that under unfavorable conditions, i.e., a limited nutrient supply, or oxygen deprivation, Mycobacterium assumed a swollen appearance without forming the vacuolar or globoid bodies. Advances in microscopic technique i.e., transmission electron microscope (TEM), scanning electron (SEM) and atomic force microcopy (AFM), have shown that the bacillus does not always manifest itself in the classical rod shape (
They become shorter in older cultures, filamentous within macrophages and ovoid during starvation [
Globally, the mortality attributed to tuberculosis was reported to be about 4700 per day and accounted for 1.7 million deaths in 2009. However, in 2011, there were an estimated 8.7 million new cases of tuberculosis and 1.4 million deaths from TB [
M. tuberculosis infection occurs via aerosol, and inhalation of only a few droplets containing the tubercle bacilli is sufficient for the pathogen to infect the lungs (
Subsequently, the pathogenesis of M. tuberculosis infection occurs in two stages. The first stage, latent TB, an asymptomatic state that can persist for many years in the host, requiring only a weakened immune response to become activated [
The parameters of the SWOT concept (the Strengths, the Weaknesses, the Opportunities and Threats) were first defined, and numerous research publications on Mycobacterium tuberculosis were reviewed to identify the parameters as applicable to the bacterium. The identified factors were then allocated to each parameter as they were determined, and discussed.
The Strengths of M. tb are the biological characteristics or attributes of internal origin which are helpful in achieving the pathogenic objective, the survival and establishment of infection by the bacterium. These include:
Possession of abundant cell wall mycothiol. The mycobacteria cell wall is composed of abundant mycolic acids, complex waxes, and unique glycolipids. The mycolic acids consist of extremely long Carbon side chains (C60 to C90) joined to the muramic acid moiety of the peptidoglycan by phosphodiester bridges, and to arabinogalactan by esterified glycolipid linkages (
On solid media the colonies are raised and rough with a wrinkled surface. The cells grow either as discrete rods or as aggregates. Virulent strains tend to grow as an aggregated long arrangement called serpentine cord. Cord factor is a derivative of mycolic acids, trehalose―6, 6-dimycolate (
Mycobacterial sulfolipids, which may play a role in virulence by suppressing phagosome combination with lysosome.
Another unique constituent which may contribute to pathogenesis is Lipoarabinomannan (LAM). Purified LAM from virulent and attenuated strains of mycobacteria may differ structurally, and these differences may contribute to their varying abilities to stimulate cytokine production in mononuclear cell cultures [
The Mycothiol is a major, low molecular weight cellular thiol that is unique to mycobacteria and responsible for protection of the bacteria against oxidative stress and survival. This accounts for impermeability and resistance to antimicrobial agents, resistance to killing by acidic and alkaline compounds in both the intracellular and extracellular environment, and resistance to osmotic lysis by lysozyme [
M. tb is highly contagious and requires low infectious dose to establish infection. Tuberculosis is most commonly spread by aerosol. When a person with active pulmonary TB exhales, coughs, sneezes, or even talks, tiny droplets containing bacteria are produced that can be inhaled by others. Inhalation of these droplet nuclei can result in infection. Between 5 - 200, inhaled bacilli are usually necessary for infection. One droplet nuclei contains no more than 3 bacilli. Droplet nuclei are so small that they can remain air-borne for extended periods of time. The most effective (infective) droplet nuclei tend to have a diameter of 5 micrometers. Droplet nuclei are generated during talking, coughing and sneezing. Coughing generates about 3000 droplet nuclei, talking for 5 minutes generates 3000 droplet nuclei, while singing generates 3000 droplet nuclei in one minute. Sneezing generates the most droplet nuclei by far, which can spread to individuals up to 10 feet away [
Ability to specifically target and replicate in the macrophages facilitate survival and dissemination. As an intracellular pathogen, the establishment of a successful infection by M. tuberculosis depends on the initial encounter with the host macrophages, which represent the first line of cellular defense against microbial invasion. At the interface between mycobacterial and macrophages, the complex outermost layer of the mycobacterial cell wall probably plays a role in facilitating entry to the host cell. The bacillus binds directly to mannose receptors on macrophages via the cell wall-associated mannosylated glycolipid, LAM, or indirectly via certain complement receptors or Fc receptors. The bacterium possession of ureC gene prevents maturation of the acidic phagosomes in macrophages, while the cord factors inactivate mitochondrial membranes of phagocytes. These are thought to be major strategies that allow them to survive and multiply within macrophages. This strength can be decreased and harnessed as potential for elimination of the bacterium, by development of new integrated antitubercular drugs that prevents entry into the macrophages by either blocking the mannose receptor and/or prevent synthesis of the ureC gene products.
Ability to establish extrapulmonary multiorgan involvement rather than strictly localized infection. M. tb has the capacity to invade other organs in the body by various mechanisms. Disseminated tuberculosis (TB) is characterized by hematogenous or lymphatic spread of Mycobacterium tuberculosis from the lungs to other parts of the body. Phagocytes with ingested mycobacteria may act as vehicles, transporting the agent to various anatomical sites in the body. Infection may spread to regional lymph nodes from the initial site through lymphatics. If a caseating lesion discharges its contents into a bronchus, they may be aspirated and distributed to various parts of the lungs. If this discharge is swallowed, it would infect the stomach and intestine. Mycobacteremia disseminates bacilli to all organs (miliary distribution). This characteristic may be attributed to the survival of the bacterium in aerobic milieu, as virtually every organ in the body require oxygen. The bacteria can spread or colonize the nasopharynx after which they cross the mucosal barrier and enter the blood stream and cerebrospinal fluid where they produce inflammation of the meninges, which results into tuberculous meningitis (TBM). Many organs and bones, including the brain, pericardium, kidneys, gastrointestinal tract, and spine, can become involved and be damaged by the infection. The symptoms vary depending on the area of the body that is affected. Some examples include back pain and paralysis (spinal TB), weakness due to anemia (TB in the bone marrow), altered mental state, headache, and coma (TBM), joint pain or abdominal pain [
For laboratory diagnosis of tuberculous meningitis 2 - 5 ml of cerebrospinal fluid can be withdrawn from patients using a lumbar puncture and subjected to routine bio-chemical analysis and pathological analysis like AFB, culture and western blot using SDS-PAGE to reveal increased protein, decreased glucose, lymphocytic predominance, presence of Mycobacterium tuberculosis, as well as a 30-KDa protein band antigen that is specific to Mycobacterium tuberculosis as a marker for tuberculous meningitis, respectively. Treatment must be started as soon as there is reasonable suspicion of TBM while waiting for confirmation of the diagnosis, as delay may lead to mental retardation, cranial nerve palsies and organic brain syndrome in adults [
Difficulty in the characterization of active TB. Part of the reason why latent TB is a relatively neglected area of research is that it is difficult to characterize. Early studies of latent TB were based on autopsy of lung tissue samples, which gave confusing results, differing greatly from one study to the next [
Ability of M. tb to shift to glyoxylate pathway during lipid metabolism in lieu of glucose, during persistence phase in the host. Persistence may be defined as a stage where the metabolic downshift to anaerobiosis brings about a nutritionally suspended condition. In the granulomas, the bacterium does not replicate and becomes inert yet surviving in occult forms to get activated in immune-compromised situations. In persistent phase the substrate is changed from glucose to lipids, glycolysis is decreased and the glyoxylate shunt is upregulated allowing anaplerotic maintenance of the tricarboxylic acid (TCA) cycle [
Dual polymorphism. Mycobacterium tuberculosis exists in actively replicating or latent states. The bacteria colonies live in a mix of these states, the proportion affecting whether an infected person exhibits symptoms. In latent TB, a person does not fall ill unless the bacteria develop into the active form, which happens to 1 in 10 infected people. In active TB, the bacteria divide, causing damage and disease; while in latent TB the bacteria lie dormant. This led to the realization that the non-replicating bacteria constitute a significant part of the problem in treating active TB. The drug treatments regime of TB takes an arduous six to nine months, because in the early month, the drug eliminates all the actively replicating bacteria, but has to be extended to kill the non-replicating bacteria. M. tuberculosis is only vulnerable when it is dividing. If the drug happens to be there when it replicates, then it can be inactivated. As the drugs require the cells to be metabolically active to be potent, current TB drugs cannot kill the bacteria when latent, which may explain why treatment regimes require six to nine months and may not completely eliminate the infection. Therefore, drugs that target both the active and latent forms could make eliminating TB a realistic goal.
Ability of the bacterium to assume variable metabolic states: dormancy, latency, persistence, stationary phase and non-replicating persistence. The ability to adapt to different conditions is a key for M. tuber-
culosis to successfully infect human hosts. Adaptations allow the organism to evade the host immune responses during acute infections and persist for an extended period of time during the latent infectious stage. Although these terms could signify the same, they describe to some extent different states and circumstances related to Latent Tuberculosis Infection (LTBI). (LTBI) is usually defined as presumptive infection with M. tuberculosis complex, as evidenced by a positive tuberculin skin test reaction and/or a positive interferon-γ release assay (IGRA) without any sign of overt disease [
Delayed seeding from the lungs of the replicating bacteria cells to the mediastinal lymph nodes. The immune response against M. tuberculosis are mainly directed against the growing bacilli [
Delayed macrophage apoptosis prior to bacterial growth and ultimate cellular necrosis. All of the growing machinery of M. tuberculosis seems to be adapted to being phagocytosed by macrophages in order to start intracellular growth [
Intrinsic resistance of non-replicating bacilli. These bacillary forms are more resistant to stress than the growing bacilli [
Growth in microaerophilic condition. Contrary to the previous belief that the bacterium was strictly aerobic, there are numerous experimental indicators that the bacterium can grow in microaerophilic environments, especially during the later stages of infection, e.g., in lung granulomas. Wild type M. tuberculosis has been shown to possess an inducible nitrate reductase which allows respiration using NO3 as a final electron acceptor. If anaerobic or microaerophilic growth is an important feature of M. tuberculosis physiology during infection, the existence of nitrate reductase could be a significant factor in sustaining growth under these conditions [
Antigenic mimicry via Antigen 85 complex. This complex is composed of a group of proteins secreted by M. tb that are known to bind fibronectin. These proteins may aid in walling-off the bacteria from the immune system and may facilitate tubercle formation.
Expression of adhesins is central to pathogenesis. Multiple M. tuberculosis proteins capable of interacting with receptors on host cells to facilitate binding to mammalian components have been identified. These include laminin binding protein involved in cyto-adherence by its recognition of laminin. Glyoxalate pathway enzyme, malate synthase (glcB; Rv1837c), binds to the human ECM proteins laminin and fibronectin and is an anchorless adhesin. The 19 kDa lipoprotein antigen (Rv3763) present on the cell wall preferentially binds to THP-1 macrophage-like cells. The cell surface glycoprotein alanineproline-rich antigen (Apa, Rv1860), initially considered a secreted molecule, has been shown to transiently associate with the cell wall to allow attachment to the pulmonary surfactant protein-A (PSP-A). The Cpn60.2 molecular chaperone protein (GroEL2; Rv0440), believed to be involved in bacterial pathogenicity and considered essential for cell viability appears to be necessary to facilitate efficient bacterial association with macrophages. Kumar et al. [
The most characterized and major adhesin in M. tuberculosis is the 28 kDa heparin-binding haemagglutinin adhesion (HBHA). This is a surface-exposed protein, a virulence factor that facilitates the dissemination of M. tuberculosis from the site of primary infection by initiating interaction with host epithelial cells. The two crucial steps in TB pathogenesis, namely bacterial aggregation and cell adhesion, are facilitated by HBHA [
The Weaknesses of M. tb are the attributes of internal origin and requirements for achieving pathogenic objective, survival and establishment of infection, which invariably are harmful, and present as potential targets for
elimination of the bacterium. These include:
M. tb requirement of a membrane protein called Rv3671c during in vivo replication. Rv3671c protein enables M. tb survival in the acidic milieu of the macrophages/phagosome. In ex vivo environment, the bacterium does not depend on the protein under standard growth conditions. However, in a susceptible host cell’ alveolar macrophages, without Rv3671c, the bacterium becomes acidified and is killed [
M. tb is a fastidious slow growing bacterium with long generation time. M. tuberculosis in vivo would most probably be limited for oxygen and nutrients, and therefore would display rather long generation times. However, in laboratory-grown cultures, these constraints do not exist and yet M. tuberculosis generation time is ~18 h on the average, while M. smegmatis divides every 3 to 5 h. Multiple properties of the tubercle bacillus contribute to its slow growth, and the unique composition of the mycobacterial envelope is likely to present permeability barriers. Since cell wall lipids constitute a high proportion of the dry weight of mycobacteria [
Establishment of productive infection in less than 10% of infected persons. Epidemiological data shows that most of M. tuberculosis infected population neither develops disease nor becomes infectious, and clinical disease occurs in less than 10% of infected persons. This suggest that genetic differences in the host determine immunological response, disease severity, and ultimate outcome of infection with mycobacteria. The interaction between M. tuberculosis and phagocytic cells results in a dynamic balance between the host defense system and the virulence factors of mycobacteria allowing the persistence of M. tuberculosis in the absence of disease. However in about 10% of M. tuberculosis infected persons, the interaction between macrophages and the tubercle bacilli may result in tissue damage characterized by tissue necrosis with the formation of cavities and dissemination of the pathogen [
M. tuberculosis is a strictly intracellular pathogen. This is an effective means of evading the immune system, particularly the ineffective antibodies and complement. In addition intracellular growth of M. tuberculosis makes it difficult for the drugs to reach the bacilli.
Mycobaterium requirement of Rm1A enzyme for growth. The mycobacterial cell wall is a complex structure composed of peptidoglycan, arabinogalactan and mycolic acids. The D-N-acetylglucosamine?L-rhamnose disaccharide connects the galactan region of arabinogalactan to the peptidoglycan via a phosphodiester linkage, critical to the structural integrity of the cell wall for mycobacterial viability. The biosynthesis of dTDP rhamnose is catalysed by four enzymes, and the first reaction is catalysed by rmlA gene encoding D-glucose-1-phosphate thymidylyltransferase (RmlA). The rm1a gene is essential for mycobacterial growth and lack of RmlA activity has profound negative effects on bacterial cell morphology and integrity [
Macrophages are the major host cell for mycobacterial infection. When successful, macrophages eliminate mycobacterial infection through a complex network of events involving tumor necrosis factor (TNF-a) production, leading to apoptosis of infected macrophages. Mycobacteria enter macrophages using various receptors, including complement receptors (CR1, CR3 and CR4), mannose receptor, CD14, Fc receptors and scavenger receptors. A recent study by Fratazzi et al. [
Variable level of adenosine triphosphate. A high level of these energy molecules is required when M. tuberculosis is actively replicating. But when latent, the bacterium requires lower levels of ATP to power its basic functions. If the level is further reduced even a bit, that may kill the organism. This is a potential “Achilles heel” for the non-replicating bacteria as maintaining ATP levels for their core metabolism is vital.
Exploitation of malate synthase (glcB; Rv1837c) in the glyoxalate shunt. The glyoxalate shunt, a key pathway in fatty acid metabolism of M. tuberculosis during persistent infection, has long been hypothesized to be a weakness in the bacteria’s armour that could potentially be exploited for the development of anti-tubercular therapeutics [
The Opportunities harnessed by M. tb are the attributes of the environment, particularly the host factors which are external in origin but helpful in achieving the pathogenic objective, survival and establishment of infection by the bacterium. These include:
Behavioral indulgence in risk factors such as smoking and alcohol consumption. Both globally and regionally, TB and MDR-TB occur among men than women owing to risk factors such as smoking, alcohol consumption or imprisonment [
Limited efficacy and use of BCG Vaccine. Bacille Calmette Guérin (BCG), the live attenuated form of M. bovis―the only vaccine so far available against TB was first introduced in 1921. It was developed in the 1920’s by two French scientists (Albert Calmette and Camille Guerin). This vaccine provides a good protection against childhood tuberculosis. However, its efficacy has been questionable in preventing pulmonary disease in adults, especially in periequatorial regions of the developing world [
Development and spread of antibiotic resistant strains as a result of non compliance to drug regimen. M. tuberculosis may be resistant to one or more drugs commonly used to treat TB. If the bacteria are resistant to more than one of the primary drugs used for therapy, the organisms are called multidrug-resistant TB (MDR- TB), and if the organisms are resistant to multiple first and second lines of therapy, they are called extensively drug-resistant tuberculosis (XDR-TB). Multidrug- and extensively drug-resistant tuberculosis (M/XDR-TB) is a man-made phenomenon that emerges as a result of inadequate treatment of tuberculosis and/or poor airborne infection control in health care facilities and congregate settings. In 2009, almost 330,000 new and relapsed cases of TB (5.6% of the global burden) and more than 46,000 deaths due to TB were reported in the WHO European Region, the majority of them in 18 countries which have made it a high priority to stop TB [
Lack of automated rapid methods for diagnosis of TB and rifampicin resistance. Current methods of TB diagnosis involving examination of sputum samples for the tubercle bacterium are labour intensive. A cheap, quick and reliable method that could be easily used in developing countries is needed. Scientists from New Zealand recently reported that honeybees could be trained to detect some of the volatile compounds released by laboratory grown M. tuberculosis. It remains to be seen whether these volatile compounds are also released during disease, and the practicability of the research. However, if the compounds are present in detectable concentrations in the breath of TB patients, then this could be a game-changer in the battle against this pathogen [
MDR-TB is under-diagnosed in children, with a consequent risk of drug resistance spreading in some regions and poor contact-tracing in some settings. There is a lack of paediatric diagnostic tools and inadequate surveillance and reporting of TB in children. TB care for children is not consistently integrated into HIV and primary health care and maternal and child health programmes. Patient-centred approaches are not fully established in most high-burden MDR-TB countries and there is a lack of mechanisms/initiatives for community - based treatment [
The pathogenic synergy of coinfection of the Human Immunodeficiency Virus (HIV) and Mycobacterium tuberculosis. These pathogens induce the acquired immunodeficiency syndrome (AIDS) and tuberculosis (TB) respectively, the two major communicable diseases with severe public health impact worldwide. Estimates of the World Health Organisation (WHO) and UNAIDS reveal a prevalence that around 33 million individuals were infected with HIV and one third of the world’s population carries M. tb. While both infections represent global public health problems in their own right, their combination is particularly threatening due to considerable mutual interactions: In HIV-positive individuals infected by M. tb, the risk to develop active TB is 21 - 37 times higher than that of the HIV-negative population [
Difficulty of TB screening in HIV-infected persons. HIV-infected TB patients often lack classic TB symptoms. Up to 30% of HIV-infected TB patients with pulmonary TB have a normal chest radiograph. Sputum smears may be negative in 50% or more and currently, no internationally accepted, evidence-based approach to screening [
Immigration. Unfavorable economic winds, wars and civil strives are the major driving forces in emigration particularly of people whose TB status are not known, from one country to the other. Collaboration mechanisms for a continuum of care between countries (cross-border TB control, migrant labour) are lacking or inadequate. TB can affect anyone, but it is most common among immigrants from countries with high levels of TB. Undiagnosed smear-positive patients are the main source of secondary infection in most communities. TB can therefore be considered an environmental problem in which TB bacilli, spread by undiagnosed or ineffectively treated contagious cases. It represents a pollutant that spoils the quality of the air and makes it unhealthy for all community members putting them at risk of infection. Compulsory testing and certification from TB infection can be mandated (as travel restriction is not acceptable) for immigrants, as necessary measures to curtail the opportunity for dissemination of the disease.
Immune status of the host. People whose immune systems are weak because of debilitating illness, medications that affect the immune system, infancy, old age, malnutrition, unhygienic or crowded living areas, alcoholism, or intravenous drug abuse highly predispose the susceptible host to M. tb infection and development of active disease.
Stigmatization. Public health education is inadequate, leading to a prevailing stigma. Individuals with TB symptoms such as a persistent cough often face significant social and economic barriers that delay their contact with health systems in which an appropriate diagnosis might be made, including difficulties in transport to health facilities, fear of stigmatization if they seek a TB diagnosis, and lack of social support to seek care when they fall sick. Stigma and discrimination associated with MDR-TB worsen adherence to treatment.
Malnutrition, poverty, homeless people living in crowded, unclean conditions are vulnerable to infection. TB is one of the ailments categorized as diseases of poverty. The association between malnutrition and disease is well recognized, but the explanation for the association is complex. Energy needs of TB patients are increased because of the disease itself. The current recommendations for TB patients are based on the nutrient and energy requirements for hyper catabolic and undernourished patients. (Approximately 35 - 40 kCal per kilogram of ideal body weight). The protein intake of the diet is important to prevent the wasting of body stores (for example muscle tissues). An intake of 1.2 - 1.5 g per kilogram body weight or 15% of energy of total daily intake or approximately 75 - 100 g per day will be sufficient. A good multivitamin and mineral supplement, providing 50% - 150% of the recommended daily allowance, is advisable. However, susceptible subjects in high TB impacted regions of the world live in poverty as they could not even afford the specified basic needs in the “Maslows Hierachy of Human needs’’ and are therefore vulnerable to TB infection. These factors are potential opportunities on which TB rides for sustenance and dissemination of the infection. Marginalized populations (homeless, migrants, etc.) and vulnerable groups (such as children and pregnant women) lack access to adequate diagnosis and treatment. Consistent intake of balanced diet, consistent income, comfortable home, living environment, regular exercise and healthy living are crucial to wall-off infection and diseases. Alli et al. [
Anatomical vulnerability of the lungs. The lungs are particularly vulnerable to infection due to limitations in anatomical barriers allowing for airflow, making effective, but non-pathologic, pulmonary immunity that is vital for successful host defense [
Slow response of the cellular immune response in M. tb. The first components of host defense to encounter pathogens that have breeched anatomical barriers constitute innate immunity which includes mononuclear phagocytes, natural killer cells and other innate cells of lymphoid origin, neutrophils, and serum factors including complement and natural antibodies. Encounter with foreign microbes through conserved pattern recognition receptors activates innate sentinels known as dendritic cells to stimulate T- lymphocytes, which in turn provide help to B-cells and orchestrate adaptive immune responses. Adaptive immunity has evolved in vertebrates to include both cellular and humoral components, with T- cells and B-cells mediating these effects, respectively. T- cells target and promote apoptotic killing of pathogen-infected cells either directly or through cytokine activation of neighboring immune cells, whereas B- cells synthesize antibodies that neutralize invasion and target infectious agents for destruction [
The global prevalence of tuberculosis. TB is a worldwide health problem. 27% of the global population (about 1.9 billion people) currently has latent TB, and 80% of the global burden is borne by only 22 countries of which India and China bear one-third of the total TB burden [
Aerosols by inspired air are crucial for latent tuberculosis infection. Production of aerosols is usually linked to the spread of the disease in the human population. Aerosols serve the function of conditioning the inspired air [
TACO assisted entry. Mycobacterium tuberculosis is internalized by host macrophages and are able to survive intracellularly because of their ability to recruit and retain a protein called TACO (tryptophane aspartate- containing coat protein) at the mycobacterial phagosome. TACO prevents vesicle fusion with the lysosomes that would normally destroy intracellular bacteria. Mycobacteria preferentially enter cells at cholesterol-rich areas of the cells’ plasma membrane and are subsequently sequestered in TACO-coated phagosomes, preventing lysosomal delivery and promoting bacterial survival. Agents designed to target the cholesterol-mediated entry of M. tuberculosis may be developed as tuberculosis therapeutics [
Interplay of host and pathogen factors. The survival and long-term persistence of M. tb within the host macrophage involves a dynamic equilibrium between competing processes initiated by the host cell at one end, and by the pathogen on the other. Various factors that regulate the course and outcome of infection are manifold and involve a complex interplay between the immune system of the host and survival strategies by the bacteria. In response to infection, the host macrophage initiates a range of anti-microbial responses. These include the phagosome-lysozome fusion pathways, activation of the autophagic machinery, generation of reactive oxygen/ni- trogen species, and induction of processes leading to cell apoptosis, among others. Therefore, survival of the intracellular M. tb depends upon its capacity to attenuate these host bactericidal pathways. In addition, the pathogen is also required to manipulate the metabolic machinery of the host cell, so as to ensure a nutrient rich environment that promotes its sustenance [
Covert existence of Smear-Negative Multidrug Resistant Tuberculosis (snMDR-TB). snMDR-TB patients are defined as smear-negative pulmonary TB (SN-PTB) patients whose clinical profiles are similar to those of MDR-TB patients, and have the potential possibility to become a MDR-TB patient. The basic issues about snMDR-TB are how to determine whether a patient is snMDR-TB and how many snMDR-TB cases there are in the real world. The majority of new TB cases (80%) occurred in 22 countries and substantial proportion (35%) were identified as SN-PTB [
Helminthic infection downregulates immunity, clinical response and vaccination against tuberculosis. Despite efforts to control TB and helminthiasis, both diseases are still the major global health problems especially in sub- Saharan Africa [
Macrophage activation can be divided into classical Th1 mediated and alternative Th2-mediated pathways. Classically activated macrophages (CAMs) up-regulate nitric oxide synthase (NOS), which oxidizes l-arginine to nitric oxide and citrulline. Nitric oxide promotes killing of intracellular M. tb [
The Threats to M. tb are the attributes of the environment which are external in origin but inimical to the pathogenic objective, survival and establishment of infection by the bacterium. These include:
The development and use of sensitive combination of microbiological tests as the gold-standard for diagnosis. This is particularly applicable in HIV infected patients. The tests may include, 2 sputum smears, chest radiography, CD4+ counts.
Evolution of specific diagnostic methods to detect mycobacteria. A cocktail of tests have been developed for the diagnosis of TB; namely, Acid-fast bacillus smear, TB Screening Tests, Bacterial Wound Culture; Susceptibility Testing, Mycobacteria tuberculosis nucleic acid amplification test (TB NAAT), Body Fluid Analysis, Sputum Culture, Adenosine Deaminase, Chest Radiography, Ultrasonography and Enzyme-Linked Immunosorbent Assay. A Quantiferon (QFT-g) test was approved in 2005 by the US Food and Drug Administration (FDA) that basically detects the presence of interferon gamma release protein (IFN-g) from the blood of sensitized patients when incubated with the early secretory antigenic target-6 (ESAT6) and culture filtrate protein 10 (CFP10) peptides [
Annual TB test. The Centers for Disease Control and Prevention recommends that people at high risk for TB (such as those with HIV infection or immigrants from areas with high rates of TB) get a skin test yearly so that treatment can begin immediately if they are found to have TB.
Prioritizing genomic drug targets in Mycobacterium tuberculosis. The search for drugs to prevent or treat infections remains an urgent focus in infectious disease research. Traditional prioritization approaches to drug target identification, such as searching the literature and trying to mentally integrate varied criteria, can quickly become overwhelming for the drug discovery researcher. This can be overcome by computationally integrate different criteria to create a ranking function that can help to identify targets. This approach has been applied on the genome of Mycobacterium tuberculosis, to evolve new drug treatments because of emerging drug-resistant strains. The cost of research and development in the pharmaceutical industry has been rising steeply and steadily in the last decade, but the amount of time required to bring a new product to market remains around ten to fifteen years [
Development of a seemingly elusive vaccine. As of now, no promising vaccine has come in to the scene so far for tuberculosis in spite of various attempts in coming up with a DNA vaccine [
Live imaging using computer tomography and positron electron tomography. Part of the reason why latent TB is a relatively neglected area of research is that it is difficult to characterize. Early studies of latent TB were based on autopsy of dead patients, the results of which gave confusing results that were different greatly from one study to the next. To overcome these challenges, advanced techniques were developed. Live imaging is a particularly exciting development, using CT (computerized tomography) and PET (positron emission tomography) scanners to look directly at TB lesions developing in the lungs of patients. PET scans illuminated areas of inflammation using radiolabelled tracers, while CT takes high-resolution X-ray images of the body, allowing the 3D structure of the scanned region to be reconstructed. These are widely used in cancer therapy, but have not been applied previously to infectious diseases such as TB. Using this combination of CT and PET imaging every single lesion in a patient can be seen, measure, study its functional status, and then treat the patient with drugs, and observe if the lesions heal or get worse.
Development and application of Infecton for imaging deep seated infections. A new radioimaging agent, Tc-99m ciprofloxacin (Infecton) has been developed to detect deep-seated bacterial infections, such as intra-abdominal abscesses. Patients with suspected bacterial infection have been subjected to Infecton imaging and microbiological evaluation, reporting an overall sensitivity of 85.4% and a specificity of 81.7% for detecting infective foci. Sensitivity was higher (87.6%) in microbiologically confirmed infections. Infecton may aid in the earlier detection and treatment of deep-seated infections such as TB, and monitoring clinical response and optimising the duration of antimicrobial treatment [
Selective isolation of TB patients by reintroduction of sanatoria to provide state-of-the-art palliative care to dying patients in a safe and dignified setting. In this way, destitute people for whom treatment has failed could voluntarily reside on a long-term basis with social, educational, and recreational facilities, and receive good nutrition and care within an infection-controlled setting, thereby reducing transmission within the community and to family members. Furthermore, avoiding close contact with people infected with TB until they are no longer contagious and use of Personal protective equipment such as a facemask (called respirator) that can prevent the spread of TB if close contact with someone who has TB is necessary. This is important in the curtailment of occupational hazards and hospital acquired infections.
Global integrated innovative approaches are required to combat and sabotage one of the oldest, deadly, and most resilient enemies of the mankind. At the level of individual, M. tuberculosis impacts humans in the most productive phase of their life thereby sucking their income, decreasing the productivity and thus inflicting a great loss in human capital. On the average one person infects fifteen others before finally getting successfully treated; the death statistics is alarming with one death every twenty second. The right to health and hope is one of the fundamental rights that are robbed by this enemy of the mankind. The conquest of the Mycobacterium to the mankind needs to be the priority of the synergistic efforts by the scientific community. Innovative approaches from drug development that includes quest for effective molecular scaffolds and their derivatives, both old and new, as well as reengineering delivery strategies for the drug to penetrate the recalcitrant stubborn microbe are imperative.
Modern therapy relies on a combination of potent bactericidal agents, such as isoniazid, rifampicin and pyrazinamide, in a treatment within six to nine month duration.
Excessive use of antibiotics has given rise to a new multidrug resistant (resistance to frontline Isoniazid and Rifampicin antibiotics) and extremely drug resistant strains leading to what we call MDR and XDRTB. The complex milieu of Mycobacterium tuberculosis and its intelligent survival instinct by virtue of adaptive diversification in tuberculosis disease have been a major obstacle that hinders the development of shorter treatment regimens to eradicate the disease.
From the foregoings, it is no gainsaying the fact that TB disease burden is so enormous that scientist can no longer rely on traditional methods of research alone but explore holistic innovative research approaches, even at the molecular level, in looking for better alternatives and treatment modules to address the issue of this pathogen.
The strengths of M. tb are attributes of internal origin of the bacterium, which are helpful to achieve the pa-thogenic objective, while the weaknesses are also attributes of internal origin which are harmful to achieve the pathogenic objective.
The opportunities utilized by M. tb are attributes of external origin which are helpful to achieve the pathogen-ic objective, while the threats are also attributes of external origin which are harmful to achieve the pathogenic objective and may be adapted as potentials for elimination of the bacterium.
Having identified each category of the concept, a 2 × 2 contingency table is drawn and the identified factors are allocated into each category (
Internal origin (attributes of the organization) | STRENGTHS 1) Possession of mycothiol. 2) Highly contagious at low dosage. 3) High cell wall content of mycolic acid. 4) Replicates in alveolar macrophages. 5) Extrapulmonary multiorgan involvement. 6) Dual polymorphism. 7) Variable metabolic states. 8) Delayed seeding of the bacterium to the mediastinal lymph nodes. 9) Delayed macrophage apoptosis. 10) Intrinsic resistance of the latent bacilli. 11) Shifts to glyoxylate pathway during lipid metabolism in lieu of glucose. | WEAKNESSES 1) Establishes productive infection in only 10% of infected subjects. 2) Requires host membrane proteins Rv3671c during in vivo replication. 3) M. tb is a strictly aerobic intracellular pathogen. 4) Variable levels of ATP. |
External origin (attributes of the organization) | OPPORTUNITIES 1) Antibiotic resistance owing to inappropriate drug treatment. 2) Smoking and alcohol consumption. 3) Limited efficacy of BCG Vaccine in adults. 4) Limited facility for diagnosis of TB. 5) Pathogenic synergy of coinfection with HIV. 6) Immune status of the host. 7) Immigration. 8) Malnutrition, poverty, undignified living conditions. 9) Anatomical vulnerability of the lungs. | THREATS 1) Development and application of infecton. 2) Inauguration of annual TB tests. 3) Selective isolation and reintroduction of Sanatoria. 4) Prioritizing genomic drug targets. 5) Sustenance of the global TB funds. 6) Development of potent vaccine. 7) Characterising TB using live imaging by computer tomography and positron electron micrography. 8) Development and use of sensitive microbiological tests as gold standard. |
Researchers and pharmaceutical corporations should develop collaborative researches to evolve interventions and protocols targeted at decreasing all the factors that present as strengths and opportunities for the bacterium, as indicated in
The factors identified in this present study are inexhaustive as research is a continuum. Further identification of other factors is encouraged. However, this concept provides an enduring innovative platform for a veritable paradigm shift in anti-tuberculosis research, towards the evolution of successful measures to curtail the scourge of M. tb.
All glory to God, the greatest scientist yesterday, today, and forever, the watershed of all intellects. All authors whose publications were reviewed to generate these findings.
Michael OluyemiBabalola, (2015) The Strengths, Weaknesses, Opportunities and Threats (SWOT) Analysis of Mycobacterium tuberculosis: A Systematic Review. Journal of Tuberculosis Research,03,184-205. doi: 10.4236/jtr.2015.34025