Jeffey's paper on tuberculosis

The Relationship between Humans and Mycobacterium tuberculosis.
By: Jeffrey Bruning

INTRODUCTION

In 1993, the World Health Organization (WHO) declared tuberculosis (TB) to be a public health emergency (Elston, 194). Since then, it has been estimated that at least 32% of the world’s population is infected with TB and a majority of these cases occur in overpopulated areas and countries where people live in poverty. Furthermore, in 2005, an estimated 8.8 million new infections were recorded and 1.6 million deaths occurred due to the infectious bacterium Mycobacterium tuberculosis (Mtb), Maybe mention something here that this is the human strand of TB? (ElstonYEAR OR PAGE). Most of the cases reported have been in third world countries where overpopulation of inner cities is a problem and the majority of the people live in poverty, such as sub-Saharan Africa and India.underline text TB occurs most frequently in places like sub-Saharan Africa and India. The relationship between Mtb and humans has recently been swaying toward a parasitic relationship due to the increasing rate of co-infections such as HIV.Mtb is also considered parasitic due to the increasing rate of co-infections with other diseases such as HIV.

BIOLOGY OF TUBERCULOSIS
WHAT IS TUBERCULOSIS
Tuberculosis is a common and often deadly infectious disease caused by mycobacterium, mainly Mycobacterium tuberculosisbold text. (FIRST LINE IS CONFUSING TO ME AND HOW IS FLOWS IN WITH THE REST CAUSE I THOUGHT Mtb WAS THE HUMAN FORM) TB attacks the lungs —(as pulmonary TB) but can also affectas well as other systems in the body such as the central nervous system and lymphatic system. —TuberculosisTB (CONSISTENCY WITH EITHER NAME OR ABREVIATION?) is spread through the air by infected when people who have the disease cough, sneeze, or spit. There are two stages of Tuberculosis: latent and active.(TB WILL EITHER BE IN THE LATENT OR ACTIVE STAGES) In humans, the immune response may protect against the disease; however, it will not always eradicate the infection which later may develop into active TB. The latent form of TB is when a person has the bacteria in the body and the body —keepsSUPPRESSES the bacteria in a reduced amount through the innate immune system. IF THE BODY'S INNATE IMMUNE SYSTEM IS ABLE TO SUPPRESS THE BACTERIA, TB REMAINS IN THE LATENT STAGE, OTHERWISE TB BECOMES ACTIVE. The active form of TB occurs when the bacteria number count in the body increases and the body is unable to reduce the numbers(SYMPTOMS OF ACTIVE TB)hen a person goes from latent infection to active, the symptoms generally include chest pain, a productive, prolonged cough for more than three weeks, and most commonly the person coughs up blood.
(WOULD THIS PARAGRAPH PROCEED THE ONE BEFORE?) TB is believed to have originated in prehistoric humans as a zoonotic infection which was then transmitted to humans (Neill, 1263, McKinney, 52). It is believed that the most recent ancestor of M. tuberculosis, M. Bovis, was transmitted through a milk-borne route (Neill). M. tuberculosis and M. Bovis have been determined to be 99.9% similar at the nucleotide level. The difference between the two is that humans are the only natural reservoir for M. tuberculosis whereas M. Bovis can inhabit most animals (Ernst).

RESPONSES TO TUBERCULOSIS
(THE INNATE IMMUNE SYSEM ATTEMPTS TO SUPRESS THE T. BACTERIA IN SEVERAL WAYS…)The body has many responses through the innate immune system in order to reduce the bacteria count. In pulmonary TB, the bacteria reside in the alveolar spaces of the lower lunges and are phagocytosed by resident alveolar macrophages (McKinney, 67). Mtb infects macrophages through stopping normal maturation of the phagosome thus keeping vacuole pH at 6.4 and inhibiting the destruction of the bacteria (Rhonde). After being phagoscytosedis, the bacteria canis either be destroyed or escape destruction and begin the replication process. depending on resistance from the host. Once the bacteria are able to grow within the macrophages, they must continue to inhibit the host’s innate immune response. One innate defense mechanism for the host when a bacterium is growing within a macrophage is apoptosis, or killing of the cell. (THIS IS WORDY AND CONFUSING THE WAY IT IS WRITTEN) This is done through a signal molecule which binds a ligand and signal transduction occurs. However, it is been shown that M.(AS SHOWN BY …. IF THIS WAS DONE IN A PAPER COULD YOU USE THE SCIENTIST NAME?) tuberculosis inhibits apoptosis through several different mechanisms. One way this is believed to be done is through the expression of MPT64 antigen suggesting aMPT64 protein plays a significant role. This proteinampT64 is believed to deactivate cytokines to reduce apoptosis (Mustafa, 105). Along with this(ampt64) protein, a virulent gene is believed to help stop the apoptosis of the host cell. The nuoG gene encodes for a subunit of the type I NADH dehydrogenase complex which helps inhibit apoptosis (Velmurugan 0973). This gene is also believed to affect the virulence of the bacteria. Another gene which is encoded in the DNA of the bacterium and helps the bacteria to survive is the pcaA gene. This gene encodes for a molecule which catalyses proximal cyclopropanation of α-mycolate, the mycolic acid subclass of the Mtb cell envelope (Rao, 1). This cyclopropanation of the cell envelope is critical for the development of the bacteria within the first several weeks. If this gene is absent, inflammation does not occur causing problems for the development of the bacteria. (THIS PARAGRAPH IS CONFUSING BECAUSE NEW TERMS POP UP, IT REPEATS, WORDY and some areas left hanging)
Tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) have important roles for reducing inflammation. (THE DESTRUCTION OF TISSUE CAUSED BY TB MUST BE KEPT AT A MINIMUN, THEREFORE….) It is important that pro-inflammatory responses are down-regulated to help insure the destruction of tissue caused by TB is minimal (Oh). TNF is sufficient enough to provide control of short-term infection; however, it will not control long-term infection. It (WHAT WAS FOUND?) was found that as bacterial loads increase in the host, the TNF cleaved is decreased (Marino, 1916). Moreover, the -1082A allele of the IL-10 gene may be important in determining susceptibility to TB (Oh).
The immune response is principally cell mediated which includes immune cells such as CD3, CD4, CD8, and Natural Killer cells. These different immune cells have been identified to help reduce the bacteria count within the host cells; however, it has been difficult to determine the absolute numbers of peripheral lymphocytes in adults infected with TB (Majid, 10) (Martineau). A study was conducted to determine these absolute numbers. The scientists concluded that a reduction of CD3 and CD4 cells occurred with infection of TB. This was determined by using a ratio of CD4/CD8 cells as there is no change in the number of CD8 cells, nevertheless, deficiency of CD8 can result in susceptibility to TB. It was also found that NK T cells are significantly higher in persons infected with TB. However, CD4 cells remain an important part of controlling Mtb in the host. CD4 appears to be able to exert its immunological response through the cytotoxicity partly by the production of T cell interferon gamma (INF-γ) and also by intern activation of the infected macrophage (Majid). Conversely, CD4¬¬¬¬¬+ T cells are a great way to control TB but they can be crippled and destroyed by co-infection HIV.

CO-INFECTION WITH HIV
THE PROGRESSION OF TB IS INCREASED IN INFECTED INDIVIDUALS WITH Human Immunodeficiency Virus (HIV). co-infection is one of the single greatest risk factors known for the progression of latent tuberculosis to active TB (McKinney, 59). Persons with TB infection have a lifetime risk of developing the active form; persons who have co-infection with HIV have a 5% annual risk of disease progression. (MAYBE SOMETHING ABOUT THE PARASITIC RELATIONSHIP BETWEEN THE TWO. SOMETHING LIKE,TB PARASITIZES THE IMMUNE SYSTEM BY REDUCING CD4+ T CELL COUNTS…. AT WHICH TIME HIV PROGRESSES TO AIDS )Even worse, the co-infection of HIV and Mtb may actually reinforce the progression of one another. While HIV reduces CD4+ T cell count, Mtb seems to enhance viral replication which then accelerates the progression of HIV to Acquired Immuno Deficiency Syndrome (AIDS). Mtb triggers HIV replication by activating the release of cytokines such as TNF-α which encourages viral transcription by activating the CD4+ T cells that support viral replication (McKinney, 59). While there are drugs to slow the progression of HIV, these drugs tend to be immunosuppressive, which increases the rate of the dividing bacilli and causes TB to go unchecked. It is estimated that there are 42 million cases of HIV infected people worldwide which, consequently, is enhancing the prevalence of active tuberculosis at an alarming rate (Elston, 194).

IN ORDER TO CONTROL THE TRANSMISSION OF TB EARLY AND EFFIENTLY……The aim of TB control is to break the cycle of transmission by treating TB cases as early and efficiently as possible__. However, this is not working as optimally has was hoped. Multi-drug resistance (MDR-TB) and extremely drug resistant (XDR-TB) forms of the disease are inhibiting the ability to control this world-wide disease. Cases of MDR-TB are found throughout the world while XDR-TB has recently been detected in sub-Saharan Africa (Moller, 103). In South Africa, the TB rate is ghastly with nearly 600 in every 100,000 people having acquired some form of TB (Moller, 104). WHO’s target cure rate is 85% for the control of the infection. In this area of the world, the cure rate is only 54%. One of the factors that may contribute to the low success rate is stigma caused by contrary attitudes and beliefs. Stigma in this area is a factor that depresses quality of life by undermining self-esteem. Individuals who have acquired a disease like TB are often shunned, isolated, and ridiculed. To avoid this, infected individuals often retreat from society, resulting in unfinished treatment. At the macro level, this stigma-induced, non-compliance may lead to the spread of MDR-TB or XDR-TB (Moller). (SO MUCH INFO IN THIS PARAGRAPH..JUMPS AROUND)

MAYBE A TITLE LIKE, SOCIAL CONTRIBUTIONS TO TB BECAUSE IT JUMPS (LEAPS) RIGHT INTO A WHOLE NEW SUBJECT

TB PATIENTS ARE OFTEN STIGMATIZED BECAUSE OF THEIR PHYSICAL ATTRIBUTES AND ARE OFTEN OSTRACIZED, THIS TYPE OF DISCRIMINATION IS DETRIMENTAL BECAUSE »> (SOMETHING LIKE THAT?) STIGMATIZION COMES IN SEVERAL FORMS. Stigma is not easy to define because there can be many layers that contribute to the social process (Deacon). COMPOUNDED/LAYERED STIGMA DESCRIBES PRE-EXISTING NEGATIVE PREJUDICES AND A LACK OF EDUCATION BY THE ACCUSER (SOMETHING THAT DOESN"T REPREAT STIGMA, MY SENTENCE SOUNDS MEAN (TRUE BUT MEAN)MAYBE SOMETHING ALONG THOSE LINES BUT CLEANER??) Layered stigma has been used to describe the relationship between stigma and existing forms of negative social representation and disadvantage. According to Macq, social stigma can be measured using the following layers: alienation, stereotype endorsement, discrimination, and social withdrawal. Alienation is the subjective experience of being less than a full member of society, stereotype endorsement is the degree to which people affected by TB agree with common stereotypes about people with TB, discrimination is TB patients’ perceptions of the way that they currently tend to be treated by others, and social withdrawal is the tendency of people affected by TB to isolate themselves from the rest of society (Macq).
In addition, people in the Eastern Cape of Africa believe human failure is responsible for the spread of TB due to infected persons’ carelessness and lack of discipline. People in this area believe that TB is only curable if the infected person obeys the rules, or else the infected person is “headed to the grave.” They also put THESE infected persons ARE into two categorieszed as either the irresponsible and the or blameless. The irresponsible are people who drink, smoke, and ‘enjoy life’ too much. These are the people who are usually malnourished because they spend money on unneeded things and then cannot provide for their families. This inhibits their ‘body soldiers’ or immune system from being able to fight the infection causing the disease to spread. Irresponsible persons are also those who do not seek treatment even though their symptoms can be recognized by many members of society. These people are believed to ‘selfishly’ put community members, including their family, at risk for contraction. These individual are also considered a drain on public resources, which is why they are stigmatized so heavily. On the other hand, the blameless are those who contract the disease because of the irresponsible ones. This group consists of family members and children who are born with the disease (Moller).

SOCIAL FACTORS
Immigration and poverty also have amajor impact on the spread of TB in the Eastern Cape and other parts as well as throughout of the world. MINORITY GROUPS, PARTICULARLY RECENT IMMIGRANTS FROM The majority of cases occur in minority groups, particularly recently arrived immigrants from countries with high endemicity. OFTEN IMMIGRANTS TB rates increase among persons whoHAVE liveD in poverty, smoke, are malnourished, live in poorly ventilated houses, experience social deprivation and have poor social capital INCREASING THE RATES OF TB AMOUNG THEM(Figueroa-Munoz). Monitoring these minority immigrants can increaseS awareness of TB risks. However, BECAUSE the majority of reports on screening refugees at entry points have difficulties with follow-ups, This leads to an increased number of immigrants spreading TB to citizens and causinges a significant rise in the number of infected persons (Figueroa-Munoz).

TECHNOLOGICAL RESPONSES
Because tuberculosis is a world-wide health emergency, scientists have been trying to develop cost-effective drugs for TB as well as finding for a vaccine. CD8+ T-cells are important for a host’s defense. Mtb-specific CD8+ T-cells are found at a high frequency in infected individuals but are restricted by HLA-B alleles (Lewinsohn). Because of this, Mtb is able to escape the human immune system which is why it is vital that a vaccine be developed.
Until a vaccine is developed, infected persons must rely on medicines which will help to reduce bacteria count. Two drugs are commonly used as first line defense drugs: isoniazid and rifampin. These drugs work well in most cases; however, in 1.7% of all infections, Mycobacterium tuberculosis is resistant to these first-line-of-defense drugs (Ozkutuk). The bacteria are then reported as multi-drug resistant TB (MDR-TB); therefore, the use of second-line drugs (SLDs) is required. SLDs are less effective, more toxic, and costlier than either isoniazid or rifampin. SLDs include amikacin, capromycin, kanamycin, ofloxacin, ethionamide, and clofazimine (Ozkutuk). Moreover, if Mtb is resistant to at least isoniazid and rifampin in the first-line anti-TB drugs and in addition to resistance to any fluoroquinolone and at least one of three SLDs is considered to be extensively drug-resistant tuberculosis (XDR-TB). XDR-TB is not commonly seen however, in a study on 40 strains of TB, one strain (2.5%) was found to be XDR-TB (Ozkutuk).
One way researchers are trying to deal with the spread of MDR-TB is by developing new and more effective drugs. Studies have shown that resistance to isoniazid can be due to the exclusion barrier formed by the cell wall and the outer layer (Bartzatt). In order to overcome this, Bartzatt synthesized five compounds which present slightly differing drug-like properties. This would be able to broaden the scope of clinical application. Another method for vaccine development is inhibiting Mtb metabolism. Sulfur plays a central role in numerous microbial metabolic pathways by synthesizing amino acids such as cysteine and methionine. Extracellular expression of sulfated metabolites plays important regulatory roles in cell-cell and host-pathogen communication; consequently, metabolism of sulfur is essential for mycobacterial virulence and survival. Currently, scientists are researching effective methods for inhibiting sulfur pathways which could inhibit TB growth.

Conclusion
Mycobacterium tuberculosis infects about one-third of the world’s population and infection rates are on the rise. Sociological beliefs of people throughout various regions describe TB as a curable disease if people only continue their regime of antibiotics. However, the growing prevalence of MDR-TB and new cases of XDR-TB are complicating treatment of Mtb. These drug-resistant strains along with co-infection of HIV help Mtb to evolve and become more virulent toward humans and more difficult to fight. If this continues to go unchecked, a world-wide epidemic may soon be in site. (TIE BACK TO POINTS IN PAPER, REINFORCING THE PARASITC RELATIONSHIP—-VERY GOOD AND INFORMATIVE PAPER)

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