**5.3 LCS** *versus* **HCS and IS***6110* **location**

Several reports have strongly suggested that the severity and clinical manifestations of tuberculosis depend on the immunogenicity and pathogenicity of the infecting *M. tuberculosis* strain. In this regard the IS*6110* sequence varies in number and position within the genome generating a high level of DNA polymorphism among strains.

The location of IS*6110* in *M. bovis* isolates from endogenous reactivation cases from elderly people were studied in comparison to the bovine *M. bovis* strains, concluding that the presence of more copies in human strains could be related to the adaptation from the animal to the human host (Otal et al., 2008).

In addition to the DR locus, Fomukong et al. detected a highly preferred site of insertion of IS*6110*, namely "DK1", in *M. tuberculosis* strains with low copy number. However, the prevalence of this site decreases in HCS, suggesting a separate lineage for the HCS and the LCS (Fomukong et al., 1997). This contrasted with the *M. bovis* strains analysed without copy inserted at the same genomic position that *M tuberculosis* strains (Otal et al., 2008). This agreed with the idea that LCS of *M. tuberculosis* and *M. bovis* evolved separately after the progenitor acquired IS*6110* at the DR region. According to Fomoukong *et al* (1997), among the different Beijing strains analysed until now, no IS*6110* has been detected in the DK1 locus (data not shown).

Molecular epidemiological data support the observation that the copy-number of IS*6110* in members of the MTBC may change over time. Factors affecting this rate may include the nature and duration of disease in a host and the opportunity to go through different host environments during the transmission cycle.

IS*6110* has been also checked as a tool to analyze the evolution of members of the MTBC. Transposition may have influence on the evolution of the strains, thus the parental strains should carry low copy number and the descendant, more evolved, would carry high copy number. One example that theoretically support that consideration is the Beijing family, members of this family are IS*6110* high copy-number and have shown high prevalence and high transmissibility (Mc Evoy et al., 2007). These characteristics could be seen as selective advantages of bacteria to its main purpose: infect humans (Hanekom et al., 2011). However the previous statement was theoretically possible, the presence of preferential sites, together to the presence of forbidden sites makes the study of IS*6110* variation in the genomes useless as evolutionary tool (Kivi et al., 2002).

#### **6. References**

76 Understanding Tuberculosis – Deciphering the Secret Life of the Bacilli

Because in most population-based studies the proportion of cases with isolates that have five or fewer copies of IS*6110* is low, the impact of these cases in the study of the overall

**IS6110** 

**Reference** 

et al., 2009

**Strain name Family Ner copies** 

Zaragoza MTZ U 12 Lopez-Calleja

The Netherlands Harlingen Type Haarlem 12 Kiers et al., 1997 Canarias GC1237 Beijing 19 Caminero, et al., 2001 Greenland GC2 10 Søborg, et al., 2001 New York CDC1551 4 Kelley et al., 1999

South- Africa KNZ LAM 13 Streicher et al. 2011 Argentina M Haarlem 8 Ritacco et al., 1997 Spain MBZ Bovis 2 Samper et al., 2007 New York W Beijing 23 Bifani et al., 1996

Several reports have strongly suggested that the severity and clinical manifestations of tuberculosis depend on the immunogenicity and pathogenicity of the infecting *M. tuberculosis* strain. In this regard the IS*6110* sequence varies in number and position within

The location of IS*6110* in *M. bovis* isolates from endogenous reactivation cases from elderly people were studied in comparison to the bovine *M. bovis* strains, concluding that the presence of more copies in human strains could be related to the adaptation from the animal

In addition to the DR locus, Fomukong et al. detected a highly preferred site of insertion of IS*6110*, namely "DK1", in *M. tuberculosis* strains with low copy number. However, the prevalence of this site decreases in HCS, suggesting a separate lineage for the HCS and the LCS (Fomukong et al., 1997). This contrasted with the *M. bovis* strains analysed without copy inserted at the same genomic position that *M tuberculosis* strains (Otal et al., 2008). This agreed with the idea that LCS of *M. tuberculosis* and *M. bovis* evolved separately after the progenitor acquired IS*6110* at the DR region. According to Fomoukong *et al* (1997), among the different Beijing strains analysed until now, no IS*6110* has been detected in the DK1

Molecular epidemiological data support the observation that the copy-number of IS*6110* in members of the MTBC may change over time. Factors affecting this rate may include the nature and duration of disease in a host and the opportunity to go through different host

transmission of tuberculosis in a community will be low.

Table 6. *M. tuberculosis* complex strains causing large outbreaks.

the genome generating a high level of DNA polymorphism among strains.

**5.3 LCS** *versus* **HCS and IS***6110* **location** 

to the human host (Otal et al., 2008).

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**4** 

*USA* 

Beatrice Saviola

**Response of Mycobacterial Species** 

Bacteria must be able to respond to a host of environmental stresses. The ability is vital if bacteria are to withstand insults both of an external location as well as during infection of an animal host. Many investigators study these responses individually in order to better understand pathogenic processes. Desiccation, response to UV light, heat, and cold stress can be encountered in the external environment. Low oxygen tension, heat stress, oxidative stress, nitrosidative stress, and acidic stress are all environments that can be encountered upon infection *in vivo* of a host. This review focuses on acidity as a stress which can be important in mycobacterial pathogenesis. Acidity can be found in such environments as acidic water and soil and can affect mycobacteria in an animal host. Mycobacteria encounter acidic stress at sites of inflammation and within phagosomes of macrophages. Exposure to acidic stress in the external environment may prime mycobacteria to upregulate genes involved in pathogenesis. Upregulation in response to acidic stress may prime mycobacteria

In contrast to *Mycobacterium tuberculosis* which is found exclusively in a human or animal host, environmental mycobacteria are found in the environment. Contamination of water or other environmental locations can then lead to infection. Environmental mycobacteria are in general not transmitted person to person but instead environment to person. Therefore the environmental milieu is important in priming mycobacteria for survival. If acidity is encountered in the host upon infection of a human, those genes that aid in resistance in the environment are already upregulated. Upon being engulfed by macrophages acid primed

*Mycobacterium avium* has been found to be isolated from acidic swamp waters in the Southeastern United States (Kirschner et al; 1992). *M. avium* isolates grew at pH levels as low as 4.0 and grew at acidic pHs just as well as at neutral pH (Kirschner et al; 1999). Mycobacteria have also been isolated from brook waters draining from acidic coniferous forests in Finland. Furthermore, growth seems to be negatively correlated with pH. As pH lowers there is a propensity to isolate mycobacteria (Livanainen et al; 1999). Thus low pH

to be more resistant to other stresses and to be more able to persist *in vivo*.

mycobacteria are already somewhat resistant to that *in vivo* environment.

**1. Introduction** 

**2. Environmental mycobacteria** 

**to an Acidic Environment** 

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