<p>Uvod: Povezanost dijabetesa melitusa i&nbsp; tuberkuloze je odavno primećena i bila je predmet ispitivanja mnogih studija. Dijagnoza &scaron;ećerne bolesti pre otkrića insulina značila je smrtni ishod u roku od pet godina, a najče&scaron;ći uzrok smrti su bile infekcije, uključujući tuberkulozu. Poslednjih godina incidenca tuberkuloze je u padu, ali je i dalje prisutan značajan broj obolelih od tuberkuloze u zemljama u razvoju. Sa druge strane incidenca dijabetes melitusa je u porastu, pre svega zbog tendencije porasta broja gojaznih osoba. Procenjeno je da će prevalencija obolelih od dijabetes melitusa dostići 438 miliona obolelih do 2030, a 80% svih slučajeva će biti stanovnici zemalja u razvoju gde je i dalje visoka prevalencija tuberkuloze. Kao rezultat ovakve epidemiolo&scaron;ke situacije ove dve bolesti će se sve če&scaron;će javljati uporedo, modifikujući tok jedna drugoj. Preduslov za uspe&scaron;no lečenje dijabetičara obolelih od tuberkuloze je postizanje zadovoljavajuće metaboličke regulisanosti &scaron;ećerne bolesti. smrtni ishod u roku od pet godina, a najče&scaron;ći uzrok smrti su bile infekcije, uključujući tuberkulozu. Poslednjih godina incidenca tuberkuloze je u padu, ali je i dalje prisutan značajan broj obolelih od tuberkuloze u zemljama u razvoju. Sa druge strane incidenca dijabetes melitusa je u porastu, pre svega zbog tendencije porasta broja gojaznih osoba. Procenjeno je da će prevalencija obolelih od dijabetes melitusa dostići 438 miliona obolelih do 2030, a 80% svih slučajeva će biti stanovnici zemalja u razvoju gde je i dalje visoka prevalencija tuberkuloze. Kao rezultat ovakve epidemiolo&scaron;ke situacije ove dve bolesti će se sve če&scaron;će javljati uporedo, modifikujući tok jedna drugoj. Preduslov za uspe&scaron;no lečenje dijabetičara obolelih od tuberkuloze je postizanje zadovoljavajuće metaboličke regulisanosti &scaron;ećerne bolesti. Cilj istraživanja: Cilj rada je bilo ispitivanje uticaja dijabetesa melitusa na tok plućne tuberkuloze, prvenstveno na bakteriolo&scaron;ki status, radiolo&scaron;ku prezentaciju bolesti, dužinu terapijskog režima i učestalost recidiva bolesti. Materijal i metode: Ispitivanjem su obuhvaćene dve grupe od po pedeset bolesnika koji su hospitalizovani u Institutu za plućne bolesti Vojvodine. Prvu grupu činili su bolesnici sa plućnom tuberkulozom i pridruženom &scaron;ećernom bole&scaron;ću, a drugu grupu bolesnici sa plućnom tuberkulozom bez pridružene &scaron;ećerne bolesti. Svi bolesnici su analizirani po sledećim karakteristikama: starost, pol, klinička slika, bakteriolo&scaron;ki status, radiolo&scaron;ka prezentacija, prisustvo neželjenih efekata antituberkulotika, prisustvo rezistencije M. tuberculosis na lekove, trajanje terapijskog režima, ishod lečenja, pojava recidiva i dužina hospitalizacije. Oboleli od &scaron;ećerne bolesti bili su dodatno analizirani prema: tipu bolesti, dužini trajanja bolesti, metaboličkoj regulisanosti bolesti i prisustvu komplikacija. Svi bolesnici obuhvaćeni ispitivanjem bili su podvrgnuti standardnom dijagnostičkom algoritmu koji obuhvata: anamnezu i fizikalni pregled, direktnu mikroskopiju sputuma, kultivaciju sputuma, radiogram grudnog ko&scaron;a, CT grudnog ko&scaron;a u slučaju postavljenih kliničkih indikacija. Invazivna dijagnostika će se sprovesti kod bolesnika kod kojih dijagnoza nije mogla biti postavljena prethodno sprovedenom neinvazivnom dijagnostikom. Terapijski režim će biti započet tokom hospitalizacije u Institutu za plućne bolesti Vojvodine, a nastavljen ambulantno pod kontrolom Dispanzera za plućne bolesti. Po zavr&scaron;etku terapijskog režima predviđena je kontrola u Institutu za plućne bolesti Vojvodine koja obuhvata procenu kliničke slike, bakteriolo&scaron;kog statusa, radiolo&scaron;kog nalaza i eventualnu potrebu za produženjem terapijskog režima. Rezultati: Istraživanje je pokazalo da je u grupi obolelih od tuberkuloze bez pridruženog dijabetes melitusa bio sličan broj bolesnika mu&scaron;kog i ženskog pola, a veći broj ispitanika se nalazio u starosnim kategorijama do 50 godina starosti, dok je u grupi obolelih od tuberkuloze sa dijabetes melitusom bio značajno vi&scaron;e zastupljen mu&scaron;ki pol i značajno vi&scaron;e ispitanika se nalazilo u starosnim kategorijama preko 50 godina starosti. Beleži se statistički značajno veći broj recidiva u grupi obolelih od tuberkuloze sa dijabetes melitusom (p=0,001). Između ispitvanih grupa se ne beleži statistički značajna razlika u kliničkoj prezentaciji bolesti. U grupi obolelih od tuberkuloze sa dijabetes melitusom, statistički značajno je veći broj direktno pozitivnih nalaza sputuma (p=0,046). Utvrđeno je postojanje statistički značajne razlike u prosečnoj dužini vremena potrebnoj za direktnu konverziju sputuma (p=0,000) i prosečnoj dužini vremena potrebnoj za konverziju kulture sputuma (p=0,000). U oba slučaja je grupa obolelih od tuberkuloze sa pridruženim dijabetes melitusom imala duže prosečno vreme potrebno za konverziju. U grupi obolelih od tuberkuloze sa pridruženim dijabetes melitusom bilo je statistički značajno vi&scaron;e bolesnika sa prisustvom kaverne (p=0,006) i lokalizacijom promena u sva tri režnja (p=0,000). Nije zapažena statistički značajna razlika u trajanju terapijskog režima, ispoljavanju neželjenih efekata lekova, pojavi rezistencije na lekove i ishodu lečenja između dve ispitivane grupe. Grupa obolelih od tuberkuloze sa pridruženim dijabetesom imala je statistički značajno veći broj bolničkih dana (p=0,000). Poređenjem grupa obolelih od tuberkuloze sa pridruženim zadovoljavajuće regulisanim dijabetesom i grupe obolelih od tuberkuloze sa lo&scaron;e regulisanim dijabetesom uočeno je statistički značajno duže trajanje terapijskog režima kod dijabetičara sa lo&scaron;e regulisanom bole&scaron;ću (p=0,018). Nije bilo statistički značajne razlike u zastupljenosti recidiva, kliničke prezentacije bolesti, bakteriolo&scaron;kog i radiolo&scaron;kog statusa, ispoljavanju neželjenih efekata lekova, pojavi rezistencije na lekove, ishoda lečenja i broja bolničkih dana između dve ispitivane grupe. Dodatnim poređenjem grupa (oboleli od tuberkuloze bez pridruženog dijabetesa, oboleli od tuberkuloze sa pridruženim zadovoljavajuće regulisanim dijabetesom i oboleli od tuberkuloze sa pridruženim lo&scaron;e regulisanim dijabetesom) primećeno je da je grupi bolesnika obolelih od tuberkuloze sa lo&scaron;e regulisanim dijabetesom potrebno najduže vreme za direktnu konverziju i konverziju kultura sputuma na MT i da imaju najveći broj bolničkih dana. U grupi obolelih od tuberkuloze sa pridruženim lo&scaron;e regulisanim dijabetesom je bilo statistički značajno veći broj bolesnika koji su lečeni osam meseci u odnosu na druge dve grupe (p=0,011). Poređenjem grupa obolelih od tuberkuloze sa tipom 1 dijabetesa tipom 2 dijabetesa nije uočena statističk značajna razlika između grupa po svim ispitivanim varijablama. U grupi dijabetičara sa dobro regulisanim dijabetesom nalazi se veći broj onih koji imaju tip 2 bolesti, u odnosu na grupu bolesnika sa lo&scaron;e regulisanim dijabetesom. Grupa dijabetičara sa lo&scaron;e regulisanom bolesti ima statistički značajno veći broj komplikacija &scaron;ećerne bolesti. Zaključak: Dokazano je da &scaron;ećerna bolest značajno utiče na bakteriolo&scaron;ki status, radiolo&scaron;ku prezentaciju, dužinu terapijskog režima, učestalost recidiva tuberkuloze i broj bolničkih dana obolelih od tuberkuloze,kao i da je regulisanost &scaron;ećerne bolesti imala značajan uticaj na dužinu terapijskog režima.</p> / <p>Introduction: The association of diabetes mellitus and tuberculosis has long been observed and has been the subject of many studies. The diagnosis of diabetes before the discovery of insulin meant death within five years, a leading cause of death were infections, including tuberculosis. Last years the incidence of tuberculosis has declined, but there is still a significant number of TB patients in developing countries. On the other hand, the incidence of diabetes is on the rise, primarily due to the tendency of an increasing number of obese people. It is estimated that the prevalence of patients with diabetes will reach 438 million sufferers by 2030, and 80% of all cases will be people in developing countries where it is still a high prevalence of tuberculosis. As a result of the epidemiological situation, these two diseases will increasingly occur in parallel, modifying the current one another. Aim: The aim of this study was to investigate the influence of diabetes mellitus on the course of pulmonary tuberculosis, primarily in the bacteriological status, radiological presentation of disease, duration of the treatment regimen and the frequency of disease relapse. Materials and Methods: The study included two groups of fifty patients who were hospitalized at the Institute for pulmonary diseases. The first group consisted of patients with pulmonary tuberculosis and concomitant diabetes mellitus, a second group consisted of patients with pulmonary tuberculosis without associated diabetes. All patients were analyzed by the following characteristics: age, gender, clinical picture, bacteriological status, radiological presentation, the presence of side effects of antituberculosis drugs, the presence of M. tuberculosis resistant to the drugs, the duration of the therapeutic regimen, treatment outcome, recurrence and length of hospitalization. Diabetics were further analyzed with respect to: the type of disease, duration of disease, a metabolic disease and the regulation for the presence of a complication. All patients completed this study were subjected to a diagnostic algorithm comprising: history and physical examination, direct microscopy of sputum, cultivation of sputum, radiographs of the chest, chest CT scan in case positioned on clinical indications. Invasive diagnostic will be performed in patients in whom the diagnosis could not be set previously conducted noninvasive diagnostics. The treatment regimen will be started during the hospitalization in the Institute of pulmonary diseases and is set under the control of ambulatory pulmonary dispensaries. Results: The study showed that in the group of TB patients without concomitant diabetes mellitus was a similar number of patients male and female, a greater number of respondents was in the age groups up to the age of 50, while in the group of TB patients with diabetes mellitus was significantly more frequent male half and significantly more respondents were in the age groups over 50 years of age. Significantly higher number of relapses is recorded in a group of TB patients with diabetes mellitus (p = 0,001). Between the two study groups was not significant difference in the clinical presentation of the disease. In the group of TB patients with diabetes mellitus, is statistically significant higher number of smear positive findings (p = 0,046). There is a statisticaly significant difference in the average length of time required for the smear conversion (p = 0,000) and average length of time needed for the conversion of sputum cultures (p = 0,000). In both cases, the group of TB patients with associated diabetes mellitus had a longer average time needed for the conversion. In the group of patients with tuberculosis associated with diabetes mellitus was statistically significantly more patients with the presence of the cavern (p = 0,006), and the localization of the pulmonary changes in all three lobes (p = 0,000). Between the two study groups was not observed a statistically significant difference in duration of the treatment regimen, the expression of adverse drug effects, develop resistance to the drugs, and the outcome of the treatment. Group of patients with tuberculosis associated with diabetes had a statistically significantly greater number of hospital days (p = 0,000). Between the groups of patients with tuberculosis associated with satisfactory controlled diabetes and the group of TB patients with poorly controlled diabetes was statistically significantly longer duration of the therapeutic regimen in diabetic patients with poor regulation of the disease (p = 0,018). There was no significant difference in the appearance of relapses, the clinical presentation of disease, the bacteriological status, radiology, the expression of adverse drug effects, develop resistance to the drugs, outcome of the treatment, number of hospital days between the two study groups. Comparing the three groups (tuberculosis without associated diabetes mellitus, TB patients with associated satisfactorily controlled diabetes and TB patients with associated poorly controlled diabetes), it was observed that the group of patients suffering from tuberculosis with poorly controlled diabetes takes the longest time to smear conversion and conversion of sputum culture and to have the highest number of hospital days. In the group of patients with tuberculosis associated with poorly controlled diabetes was significantly greater number of patients who were treated for eight months compared to the other two groups (p = 0,011). Comparing the group of TB patients with type 1 diabetes and type 2 diabetes is not a statistically significant difference between the groups in all variables. In the group of diabetic patients with satisfactorily controlled diabetes, there are a large number of those with type 2 disease, in comparison to the group of patients with poorly controlled diabetes. Group of diabetics with poorly regulated disease has a significantly greater number of diabetes comlications. Conclusion: It has been shown that diabetes mellitus has a significant effect on the bacteriological status, radiological presentation, the length of the treatment regimen, the frequency of recurrence of tuberculosis and the number of hospital days of patients with tuberculosis, and that the adjustment of diabetes had a significant effect on the length of the treatment regimen.</p>

Introdução: O Tratamento Preventivo com Isoniazida (TPI) é indicado para os pacientes com HIV/aids e infecção latente por Micobacterium tuberculosis (ILMTb) para os quais não haja contraindicação à Isoniazida. Entretanto, barreiras de acesso podem impedir que os pacientes realizem este tratamento. Objetivos: O presente estudo avaliou a taxa de acesso à prescrição médica do TPI em sujeitos com HIV/aids e ILMTb em seguimento em um serviço especializado de HIV/aids no período de fevereiro de 2005 a dezembro de 2009. Para os sujeitos que não tiveram acesso à prescrição do TPI, buscou-se, em prontuário, justificativas para esta conduta. Também foi identificado o perfil epidemiológico, clínico e demográfico dos sujeitos com HIV/aids e ILMTb e foi descrita a característica do médico que solicitou o teste tuberculínico (TT) e do que prescreveu o TPI. Métodos: No período de 02 de fevereiro de 2005 a 31 de dezembro de 2009 que estavam em seguimento no SEAP HIV/Aids foram incluídos sujeitos com HIV/Aids e ILMTB, diagnosticada através do Teste Tuberculínico (TT). Informações referentes às variáveis analisadas foram coletadas nos prontuários médicos e através de consulta ao Sistema de Informação e Gestão Hospitalar (SIGH) - Módulo Farmácia. Resultados: Foram incluídos 238 sujeitos dentre os 310 que tiveram TT > 5 mm no período do estudo. Destes, 70,6% (168) eram do sexo masculino; a média de idade foi de 42,6 anos; 88,2% (210) dos sujeitos tiveram acesso à prescrição do TPI. O acesso à prescrição do TPI foi associado à idade, ao tamanho da resposta ao TT, ao nadir de Linfócitos TCD4+ dos sujeitos em TARV e à presença de cicatriz de BCG. Sujeitos mais jovens, com resposta ao TT igual ou maior do que 10 mm e com cicatriz de BCG tiveram maior acesso à prescrição do TPI. Uma das questões a ser explorada em futuros estudos se refere aos fatores que influenciam, ou não, a decisão do profissional de introduzir este tratamento na situação em que o mesmo está recomendado tecnicamente. Conclusão: Os sujeitos mais jovens, com melhor situação imunológica de base, maior valor de resposta ao TT e com presença da cicatriz de BCG, tiveram maior acesso ao TPI. Neste estudo foi evidenciada a necessidade de que as instituições de saúde invistam em educação continuada de seus profissionais para elevarem a cobertura de ações programáticas, como é o tratamento da ILMTB, previsto nos programas nacionais de tuberculose e de HIV/aids. Além disso, é necessário que as equipes interdisciplinares atuem de forma integrada e harmônica, para garantir o acesso às ações de saúde. É possível identificar, porém muitas barreiras que restam para a serem rompidas de modo que os cidadãos que vivem com HIV/aids tenham acesso a este e aos demais tratamentos de que tenham necessidade / Background: Isoniazid Preventive Treatment (IPT) is recommended for patients with HIV/AIDS and Latent Infection by Mycobacterium tuberculosis (ILMTb) and no contraindication to isoniazid. However, access barriers may prevent patients to undergo to this treatment. Objectives: This study evaluated the rate of access to the prescription of IPT in subjects with HIV/aids and ILMTb followed up in a specialized HIV/aids from February 2005 to December 2009. For subjects who did not have access to the prescription of IPT, we sought, on records, justification for this conduct. Also, the epidemiological, clinical and demographic profile of individuals with HIV/AIDS and ILMTb and the characteristic of the doctor who requested the tuberculin skin test (TST) and prescribed IPT were identified. Methods: from 02 February 2005 to 31 December 2009 subjects followed up at SEAP HIV/aids with HIV/aids and ILMTB, diagnosed by Tuberculin Test (TST) were included. Information was collected from the medical records and from the Hospital Information and Management System (SIGH) - Pharmacy Module. Results: 238 subjects were included, among the 310 who had TST > 5 mm during the study period. Of these, 70.6 % (168) were male and the average age was 42.6 years, 88.2 % (210) had access to the prescription of IPT. Access to IPT prescription was associated with age , size of response to TST, nadir of lymphocytes CD4 + in subjects on ART and presence of BCG scar: younger subjects with response to TST equal to or greater than 10 mm and BCG scar had higher access rate to IPT prescription. An issue to be explored in the future refers to variables that influence the professional\'s decision to prescribe this treatment when it is technically recommended. Conclusion: younger subjects with better immune status at baseline, greater response to TST and presence of BCG scar, had more access to IPT. This study highlighted the need of educational programs for health professionals, in order to improve the coverage of activities devoted to reduce morbidity and mortality in HIV/aids patients, as is the treatment of ILMTB, recommended in national tuberculosis and HIV/AIDS programs. Furthermore, it is crucial, for interdisciplinary health teams, to operate in an integrated and harmonious way, to ensure, for HIV/aids patients, a healthy and longer life

Introdução: O Tratamento Preventivo com Isoniazida (TPI) é indicado para os pacientes com HIV/aids e infecção latente por Micobacterium tuberculosis (ILMTb) para os quais não haja contraindicação à Isoniazida. Entretanto, barreiras de acesso podem impedir que os pacientes realizem este tratamento. Objetivos: O presente estudo avaliou a taxa de acesso à prescrição médica do TPI em sujeitos com HIV/aids e ILMTb em seguimento em um serviço especializado de HIV/aids no período de fevereiro de 2005 a dezembro de 2009. Para os sujeitos que não tiveram acesso à prescrição do TPI, buscou-se, em prontuário, justificativas para esta conduta. Também foi identificado o perfil epidemiológico, clínico e demográfico dos sujeitos com HIV/aids e ILMTb e foi descrita a característica do médico que solicitou o teste tuberculínico (TT) e do que prescreveu o TPI. Métodos: No período de 02 de fevereiro de 2005 a 31 de dezembro de 2009 que estavam em seguimento no SEAP HIV/Aids foram incluídos sujeitos com HIV/Aids e ILMTB, diagnosticada através do Teste Tuberculínico (TT). Informações referentes às variáveis analisadas foram coletadas nos prontuários médicos e através de consulta ao Sistema de Informação e Gestão Hospitalar (SIGH) - Módulo Farmácia. Resultados: Foram incluídos 238 sujeitos dentre os 310 que tiveram TT > 5 mm no período do estudo. Destes, 70,6% (168) eram do sexo masculino; a média de idade foi de 42,6 anos; 88,2% (210) dos sujeitos tiveram acesso à prescrição do TPI. O acesso à prescrição do TPI foi associado à idade, ao tamanho da resposta ao TT, ao nadir de Linfócitos TCD4+ dos sujeitos em TARV e à presença de cicatriz de BCG. Sujeitos mais jovens, com resposta ao TT igual ou maior do que 10 mm e com cicatriz de BCG tiveram maior acesso à prescrição do TPI. Uma das questões a ser explorada em futuros estudos se refere aos fatores que influenciam, ou não, a decisão do profissional de introduzir este tratamento na situação em que o mesmo está recomendado tecnicamente. Conclusão: Os sujeitos mais jovens, com melhor situação imunológica de base, maior valor de resposta ao TT e com presença da cicatriz de BCG, tiveram maior acesso ao TPI. Neste estudo foi evidenciada a necessidade de que as instituições de saúde invistam em educação continuada de seus profissionais para elevarem a cobertura de ações programáticas, como é o tratamento da ILMTB, previsto nos programas nacionais de tuberculose e de HIV/aids. Além disso, é necessário que as equipes interdisciplinares atuem de forma integrada e harmônica, para garantir o acesso às ações de saúde. É possível identificar, porém muitas barreiras que restam para a serem rompidas de modo que os cidadãos que vivem com HIV/aids tenham acesso a este e aos demais tratamentos de que tenham necessidade / Background: Isoniazid Preventive Treatment (IPT) is recommended for patients with HIV/AIDS and Latent Infection by Mycobacterium tuberculosis (ILMTb) and no contraindication to isoniazid. However, access barriers may prevent patients to undergo to this treatment. Objectives: This study evaluated the rate of access to the prescription of IPT in subjects with HIV/aids and ILMTb followed up in a specialized HIV/aids from February 2005 to December 2009. For subjects who did not have access to the prescription of IPT, we sought, on records, justification for this conduct. Also, the epidemiological, clinical and demographic profile of individuals with HIV/AIDS and ILMTb and the characteristic of the doctor who requested the tuberculin skin test (TST) and prescribed IPT were identified. Methods: from 02 February 2005 to 31 December 2009 subjects followed up at SEAP HIV/aids with HIV/aids and ILMTB, diagnosed by Tuberculin Test (TST) were included. Information was collected from the medical records and from the Hospital Information and Management System (SIGH) - Pharmacy Module. Results: 238 subjects were included, among the 310 who had TST > 5 mm during the study period. Of these, 70.6 % (168) were male and the average age was 42.6 years, 88.2 % (210) had access to the prescription of IPT. Access to IPT prescription was associated with age , size of response to TST, nadir of lymphocytes CD4 + in subjects on ART and presence of BCG scar: younger subjects with response to TST equal to or greater than 10 mm and BCG scar had higher access rate to IPT prescription. An issue to be explored in the future refers to variables that influence the professional\'s decision to prescribe this treatment when it is technically recommended. Conclusion: younger subjects with better immune status at baseline, greater response to TST and presence of BCG scar, had more access to IPT. This study highlighted the need of educational programs for health professionals, in order to improve the coverage of activities devoted to reduce morbidity and mortality in HIV/aids patients, as is the treatment of ILMTB, recommended in national tuberculosis and HIV/AIDS programs. Furthermore, it is crucial, for interdisciplinary health teams, to operate in an integrated and harmonious way, to ensure, for HIV/aids patients, a healthy and longer life

Mycobacterium tuberculosis, the etiological agent of tuberculosis, has adapted with the host environment and evolved to survive in harsh conditions in the host. The pathogen has successfully evolved strategies not only to evade the host immune system but also to thrive within the host cells. Upon infection, the pathogen is either cleared due to the host immune response, or it survives and causes active tuberculosis (TB) infection. In a number of cases however, the pathogen is neither killed nor does it actively proliferate, but it remains dormant in the host until the environment becomes favorable. This dormant state of pathogen is responsible for latent TB infection (LTBI). WHO reports indicated that as much as a third of the whole world’s population is exposed to the pathogen, of which a significant proportion could be latently infected (WHO report, 2015). These individuals do not show symptoms of active TB infection and hence are difficult to detect. The latent TB infected (LTBI) individuals serve as a reservoir for the pathogen, which can lead to epidemics when the conditions change. Hence, it is necessary to understand the host -pathogen interactions during LTBI, as this might provide clues to developing new strategies to detect and curb a latent infection. Host-pathogen interactions are multifaceted, in which both species attempt to recognize and respond to each other, all of these through specific molecules making distinct interactions with the other species. The outcome of the infection is thus decided by a complex set of host-pathogen interactions. The complexity arises since a large number of molecular components are involved, also multiplicity of interactions among these components and due to several feedback, feed forwards or other regulatory or influential loops within the system. The complexity of biological systems makes modeling and simulation an essential and critical part of systems– level studies. Systems biology studies provide an integrated framework to analyze and understand the function of biological systems. This work addresses some of these issues with an unbiased systems-level analysis so as to identify and understand the important global changes both in the host and in the pathogen during LTBI. The broad objectives of the work was to identify the key processes that vary in the host during latent infection, the set of metabolic reactions in the host which can be modulated to control the reactivation of infection, global adaptation in Mycobacterium tuberculosis (Mtb) and then to utilize this knowledge to identify strategies for tackling latent infection. A review of literature of the current understanding of latency from the pathogen and the host perspective is described in chapter 1. From this, it is clear that most available studies have focused on the role of individual molecules and individual biological processes such as granuloma formation, toll-like receptor signaling, T cell responses as well as cytokine signaling, in either initiating or maintaining a latent infection, but there is no report till date about whether and how these processes are connected with each other. While transcriptome based studies have identified lists of differentially expressed genes in LTBI as compared to healthy controls, no further understanding is currently available for many of them, regarding the processes they may be involved in and what interactions they make, which may be important for understanding LTBI. The first part of the work is a systematic meta-analysis of genome-scale protein interaction networks rendered condition-specific with transcriptome data of patients with LTBI, which has provided a global unbiased picture of the transcriptional and metabolic variations in the host and in the pathogen during the latent infection. To start with, publicly available gene expression data related to LTBI, active TB and healthy controls were considered. In all, 183 datasets summing up to 105 LTBI, 41 active TB and 37 healthy control samples were analyzed. (Chapter 2). Standard analysis of the transcriptome profiles of these datasets indicated that there was zero overlap among them and that not a single gene was seen in common among all datasets for the same condition. An extensive human protein-protein interaction network was constructed using information available from multiple resources that comprehensively contained structural or physical interactions and genetic interactions or functional influences. Nodes in this network represented individual proteins and edges represented interactions between pairs of nodes. The identity of each node and the nature of interaction of each edge along with the type of evidence that was used as the basis for drawing the edge, was collated for the network. The gene expression data was integrated into the human protein-protein interaction (PPI) network for each condition, which essentially had weighted nodes and directed edges, specific to that condition, from which specific comparative networks were derived. The highest ranked perturbations in LTBI were identified through a network mining protocol previously established in the laboratory. This involved computing all versus all shortest paths on the comparative network, scoring the paths based on connectedness and various centrality measures of the nodes and the edges and finally ranking the paths based on the cumulative path scores. Intriguingly, the top-ranked set of perturbations were found to form a connected sub-network by themselves, referred to as a top perturbed sub-network (top-net), indicating that they were functionally linked or perhaps even orchestrated in some sense. Th17 signaling appears to be dominant. About 40 genes were identified in the unique set of LTBI condition as compared to the active TB condition, and these genes showed enrichment for processes such as apoptosis, cell cycle as well as natural killer cell mediated toxicity. Construction and analysis of a miRNA network indicated that 32 of these have strong associations with miRNA explaining the role of the latter in controlling LTBI. 3 other genes from the top-net are already established drug targets for different diseases with known drugs associated with them, which are BCL2, HSP90AA1 and NR3C1. These 3 proteins can be explored further as drug targets in LTBI whose manipulation using existing drugs may result in inhibiting the underlying biological process and thereby result in disturbing the state of latency. As a second objective, global variations in the host transcriptome were identified during ascorbic acid induced dormancy (Chapter 3). Ascorbic acid or Vitamin C is a nutrient supplement required in the diet. This organic compound has a known antioxidant property, as it is known to scavenge the free radicals. In a recent study, Taneja et al, demonstrated that Vitamin C could induce dormancy in Mtb. On similar lines, experiments were done in THP-1 cells infected with Mtb to determine the host responses during ascorbic acid (AA) induced dormancy. The raw gene expression data was provided by our collaborator Prof. Jaya Tyagi that included 0 hour, 4 days and 6 days time points with infection and vitamin C versus infection alone or vitamin C alone as controls. The transcriptome data was normalized and integrated into the human PPI network as described for the meta-analyses. It was experimentally determined that ascorbic acid induces dormancy in 4 days post infection. The top-ranked paths of perturbation were analyzed and compared for three different conditions: (i) uninfected condition, (ii) AA treated and infected condition, and (iii) AA, isoniazid and infected condition. The dormant pathogen is known to be drug-tolerant and thus as a marker for the state of dormancy, the lack of effect of isoniazid is also monitored in the infected host cells. The analysis revealed that there were some broad similarities as compared to LTBI from patient samples but AA induced dormancy in cell lines stood out a separate group indicating that there were significant differences such as involving Interferon Induced Transmembrane Proteins (IFITMs), vacuolar ATPase as well as GDF15, which belongs to TGF-beta signaling pathway. The highest ranked perturbed paths contained genes involved in innate immune responses of which ISG15, IFITMs, HLAs and ATPases emerge as the most altered in the dormant condition. CCR7 emerges as a key discriminator, which is subdued in the latent samples but highly induced in infection conditions. Pathway-based analysis of different conditions showed that oxidative stress, glutathione metabolism, proteasome degradation as well as type II interferon signaling are significantly up-regulated in AA induced dormancy. The dormant bacteria reside in the host cells and are known to modulate the host metabolism for their own benefit. So, the third objective was to understand the metabolic variations in the host during LTBI (Chapter 4). A genome-scale metabolic (GSM) model of alveolar macrophage was used in this study. The metabolic model contains information of the reactions, metabolites and the genes encoding enzymes that catalyze a particular reaction. Flux balance analysis (FBA), a constraint-based metabolic modeling method, is used for analyzing the alterations in the metabolism under different infection conditions. In order to mimic the physiological condition, gene expression data was used for constraining the bounds of the reactions in the model. Two different expression studies were used for analysis: GSE25534 (from Chapter 2) and ascorbic acid induced dormancy (Chapter 3). The analysis was carried out for latent TB versus healthy control and latent TB versus active TB to identify the most altered metabolic processes in LTBI. Differences in fluxes between the two conditions were calculated. A new classification scheme was devised to categorize the reactions on the basis of flux differences. In this chapter, higher fluxes in LTBI condition were identified for reactions involved in transport of small metabolites as well as amino acids. Solute carrier proteins responsible for the transport of the metabolites were identified and their biological significance is discussed. Reduced glutathione (GSH), arachidonic acid, prostaglandins, pantothenate were identified as important metabolites in LTBI condition and their physiological role has been described. Sub-system analysis for different conditions shows differential regulation for arachidonic acid metabolism, fatty acid metabolism, folate metabolism, pyruvate metabolism, glutathione metabolism, ROS detoxification, triacylglycerol synthesis and transport as well as tryptophan metabolism. From the study, transporter proteins and reactions altered during LTBI were identified, which again provide clues for understanding the molecular basis of establishing a latent infection. Mycoabcterium tuberculosis is known to undergo dormancy during stress conditions. In this chapter, the main objective was to identify the global variations in the dormant Mtb (Chapter 5). To carry out the analysis, the Mtb PPI network was constructed using information from available resources. Gene expression data of two different dormancy models, Wayne growth model and multiple-stress model, were used for the study. To identify the key players involved in reversal of dormancy, the transcriptome data of reaeration condition was also used. In this study, the Max-flow algorithm was implemented to identify the feasible paths or flows in different condition. The flows with higher scores indicate that more information is traversed by the path, and hence is important for the study. From the analysis of Wayne growth model (hypoxia model), important transcriptional regulators such as SigB, SigE, SigH, regulators in the two-component system such as MprA, MtrA, PhoP, RegX3 and TrcR were identified in stress condition. Multiple-stress model studied the growth of bacteria in low oxygen concentration, high carbon dioxide levels, low pH and nutrient starvation. The gene expression data was integrated in the Mtb PPI network and implementation of Max-flow algorithm showed that MprA, part of the MprA-MprB two-component system, is involved in the regulation of persistent condition. WhiB1 also features in the paths of dormant condition and its role in persistence can be explored. In reaeration model, WhiB1 and WhiB4 are present in the top flows of this condition indicating that the redox state is perturbed in the pathogen and the interactions of these proteins are important to understand the reversal of dormant condition. From the study, Rv2034, Rv2035, HigA, Rv1989, Rv1990 and Rv0837 proteins belonging to toxin-antitoxin systems were also identified in the dormant bacteria, indicating their role in adaptation during stress condition. The role of Rv2034 has been studied in persistence, but the function of other proteins can be analyzed to provide new testable hypotheses about the role of these proteins in dormancy. Thus, the flows or paths perturbed during dormancy were identified in this study. To get a better understanding of the metabolic network active in mycobacteria under different conditions, experiments were performed in Mycobacterium smegmatis MC2 155. The non-pathogenic strain of genus Mycobacteria, Mycobacterium smegmatis, is used as a surrogate to carry out molecular biology studies of Mtb. Mycobacterium smegmatis MC2 155 (Msm) is the commonly used laboratory strain for experimental purpose. In order to obtain a clear understanding of how comparable are the metabolic networks between the virulent M. tuberculosis H37Rv and the model system Msm, the latter model is first studied systematically. In Chapter 6, first the functional annotation of the Msm genome was carried out and the genes were categorized into different Tuberculist classes based on homology with the Mtb genome. A high-throughput growth characterization was carried out to characterize the strain systematically in terms of different carbon, nitrogen or other sources that promoted growth and thus served as nutrients and those that did not, together yielding a genome-phenome correlation in Msm. Gene expression was measured and used for explaining the observed phenotypic behavior of the organism. Together with the genome sequence, the transcriptome and phenome analysis, a set of about 257 different metabolic pathways were identified to be feasible in wild-type Msm. About 284 different carbon, nitrogen source and nutrient supplements were tested in this experiment and 167 of them supported growth of Msm. This indicates that the compounds enter the cells and are metabolized efficiently, thus yielding similar phenotypes. The expressed genes and metabolites supporting growth were mapped to the metabolic network of Msm, thus helping in the identification of feasible metabolic routes in Msm. A comparative study between Msm and Mtb revealed that these organisms share similarity in the nutrient sources that are utilized for growth. The study provides experimental proof to identify the feasible metabolic routes in Msm, and this can be used for understanding the metabolic capability in the two organisms under different conditions providing a basis to understand adaptations during dormancy. In the last part of the work presented in this thesis, the metabolic shift in the pathogen was studied using a genome-scale metabolic model of Mtb (Chapter 7). The model contains information of the reactions, metabolites and genes involved in the reactions. Flux balance analysis (FBA) was carried out by integrating normalized gene expression data (Wayne model and multiple-stress model transcriptome considered in Chapter 5) to identify the set of reactions, which have a higher flux in the dormant condition as compared to the control replicating condition. Glutamate metabolism along with propionyl CoA metabolism emerge as major up-regulated processes in dormant Mtb. Next, with an objective of identifying essential genes in dormant Mtb, a systematic in silico single gene knock-out analysis was carried out where each gene and it's associated reaction was knocked out of the model, one at a time and the ability of the model to reach its objective function assessed. About 168 common genes in Wayne model and multiple-stress model were identified as important in Mtb after the knockout analysis. Essentiality is in essence a systems property and requires to be probed through multiple angles. Towards this, essential genes were identified in Mtb using a multi-level multi-scale systems biology approach. About 283 genes were identified as essential on the basis of combined analysis of transcriptome data, FBA, network analysis and phyletic retention studies in Mtb. 168 genes identified as important in dormant Mtb were compared with 283 essential genes and about 91 genes were found to be essential. Finally, among the set of essential genes, those that satisfy other criteria for a drug target were analyzed using the list of high-confidence drug targets of Mtb available in the laboratory along with their associated drug or drug-like molecules. 38 out of the 168 important genes in Mtb were found to have one or more drugs associated with them from the DrugBank database. Colchicin-Rv1655, Raloxifene-Rv1653, Bexarotene-Rv3804, Rosiglitazone-Rv3804 are top-scoring drug-target pairs that can be explored for killing dormant bacilli. The study has thus been useful in identifying important proteins, reactions and drug targets in dormant Mtb. In summary, the thesis presents a comprehensive systems-level understanding of various aspects of host responses and pathogen adaptation during latent TB infection. Key host and pathogen factors involved in LTBI are identified that serve as useful pointers for deriving strategies for tackling a latent infection.