Guest guest Posted January 5, 2006 Report Share Posted January 5, 2006 Host/Pathogen adaptation is not surprising to me. I find it elegantly simple to understand that over time the host and pathogen adjust to each other. How can that NOT happen if one is infected for over 25 years as I was/am with Lyme? I think as the host's immune system ages though, the pathogen eventually gets the upper hand. I have had this though foremost in my mind as I devise ways to ambush the buggers. I intend to keep the upper hand by hook or by crook. Barb > > This paper is of vast importance to the fine science of microbicide. > To see why, start out by reading the beginning of the Discussion. > > This is free online full text. > > I'm not in a real disciplined mood here but the controls and > rationale in this paper seem tight... one possible shortcoming is > well-addressed by the authors in the final few sentences of the > Results. Also problematic is the assumption that all forms of the > organism are capable of replication in order to form colonies in the > CFU assay. This may be a huge problem. See PMID 15548322. > > I think so, but I am not quite sure whether MTB infection is > clinically pathogenic in the mice they used (the " normal " ones, not > the IFNg knockouts which MTB easily kills). This " stalemate " finding > will be much more significant to me if MTB is indeed pathogenic to > wild-type mice. On the other hand, the existence of a stalemate > involving a subclinical infection would not be surprising - because > such a stalemate is not very harmful to the host - and would be much > less suggestive reguarding the question of what is going on in our > diseases and their treatment. > > > ====================================================== > > Infect Immun. 2005 Jan;73(1):546-51. > Related Articles, Links > > > Replication dynamics of Mycobacterium tuberculosis in chronically > infected mice. > > Munoz-Elias EJ, Timm J, Botha T, Chan WT, Gomez JE, McKinney JD. > > Laboratory of Infection Biology, The Rockefeller University, 1230 > York Ave., New York, NY 10021, USA. > > The dynamics of host-pathogen interactions have important > implications for the design of new antimicrobial agents to treat > chronic infections such as tuberculosis (TB), which is notoriously > refractory to conventional drug therapy. In the mouse model of TB, > an acute phase of exponential bacterial growth in the lungs is > followed by a chronic phase characterized by relatively stable > numbers of bacteria. This equilibrium could be static, with little > ongoing replication, or dynamic, with continuous bacterial > multiplication balanced by bacterial killing. A static model > predicts a close correspondence between " viable counts " (live > bacteria) and " total counts " (live plus dead bacteria) in the lungs > over time. A dynamic model predicts the divergence of total counts > and viable counts over time due to the accumulation of dead > bacteria. Here, viable counts are defined as bacterial CFU > enumerated by plating lung homogenates; total counts are defined as > bacterial chromosome equivalents (CEQ) enumerated by using > quantitative real-time PCR. We show that the viable and total > bacterial counts in the lungs of chronically infected mice do not > diverge over time. Rapid degradation of dead bacteria is unlikely to > account for the stability of bacterial CEQ numbers in the lungs over > time, because treatment of mice with isoniazid for 8 weeks led to a > marked reduction in the number of CFU without reducing the number of > CEQ. These observations support the hypothesis that the stable > number of bacterial CFU in the lungs during chronic infection > represents a static equilibrium between host and pathogen. > > PMID: 15618194 [PubMed - indexed for MEDLINE] > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 6, 2006 Report Share Posted January 6, 2006 > I think so, but I am not quite sure whether MTB infection is > clinically pathogenic in the mice they used (the " normal " ones, not > the IFNg knockouts which MTB easily kills). Yes, it is. -------------------------------- J Med Microbiol. 1996 Aug;45(2):103-9. Related Articles, Links Persistent infection with virulent but not avirulent Mycobacterium tuberculosis in the lungs of mice causes progressive pathology. Dunn PL, North RJ. Trudeau Institute Inc., Saranac Lake, NY 12983, USA. A strain of Mycobacterium tuberculosis (H37Rv) considered virulent for mice and a strain (R1Rv) considered relatively avirulent were compared for their ability to survive host immunity in the lungs and to induce lung pathology. Although both strains of M. tuberculosis were capable of causing a slowly progressive infection in the lungs of immunocompetent mice, only the H37Rv strain was capable of inducing progressive destructive pathology and of causing loss of lung function over a 300-day period. Therefore, the ability to survive host immunity in the lungs and the ability to cause lung pathology are separate manifestations of mycobacterial virulence. PMID: 8683545 [PubMed - indexed for MEDLINE] Tuber Lung Dis. 1997;78(1):57-66. Related Articles, Links Progression of chronic pulmonary tuberculosis in mice aerogenically infected with virulent Mycobacterium tuberculosis. Rhoades ER, AA, Orme IM. Department of Microbiology, Colorado State University, USA. brhoades@... There are several critical differences in the pulmonary granulomatous response to Mycobacterium tuberculosis between the mouse and other animal models such as the guinea pig or rabbit. One key difference is a conspicuous lack of central caseating necrosis in pulmonary lesions of immunologically intact mice. To determine whether normal mice could develop such pathology in response to highly virulent clinical isolates of M. tuberculosis, C57BL/6 mice were infected aerogenically with varying doses of three different strains, and the development of a granulomatous response was followed for as long as a year. Whereas such conditions failed to induce caseating necrosis in the lungs of these mice, all of the infections induced a granulomatous response which progressed similarly. We present here a descriptive report of the gross pathological progression of tuberculosis in the lungs of the mice. In each case, the disease progressed in five discrete stages, which were delineated on the basis of several criteria including the extent of granulomatous involvement, the cell types present, the degree of lymphocyte organization, and the presence of destructive sequelae such as airway epithelium erosion and airway debris. Quicker progression of disease along these five stages was induced by increasing the size of the inoculum or by the more virulent mycobacterial strains. The infections with the virulent strains were not resolved, and the later stages of the granulomatous response coincided with an increasing bacillary load and a loss of organized lymphocytes in the infected lungs which ultimately resulted in the death of the host. These results indicate that although C57BL/6 mice do not manifest a caseating form of pulmonary tuberculosis, they manifest an equally pathogenic granulomatous response which appears as a chronic interstitial fibrosing response that fails to contain the infection at a time that organized lymphocyte involvement wanes in the lung. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted January 6, 2006 Report Share Posted January 6, 2006 Whats most interesting here to me is that this experiment suggests that taking a drug or drugs at the MIC might do you no good whatsoever if you had a low-turnover (static) infection like murine TB - where the same bacterial individuals apparently just sit and sit, keeping the mice sick, but dont grow significantly or suffer significant attrition. Perhaps a higher turnover of your pathogens, Barb, could be one reason for your successful chemotherapy. If this experiment does mean what it seems to mean, then chemotherapy which is above the MIC but below the MBC should do nothing for murine TB - but such chemotherapy should be able to cure any sort of high-turnover infection. However, since complex, often unknown factors come into play in vivo, such experimentation cannot be nearly as tidy as this description suggests. The MICs and MBCs might not translate tidily to infections of mammals. Anyway, I doubt that near-zero turnover is the sole key to our illnesses, for several reasons. I suspect the mystery phenomenon seen in the Geiffers Cpn/monocytes paper could be more central. One interesting question is whether beta-lactams can kill the non-growing organisms a near-zero-turnover infection comprises. The textbook answer would be a simple no, but I am trying to look a little deeper. And if beta-lactams really cannot affect an infection which is in stasis, then anyone benefiting from beta-lactams would have to be concluded to have an infection with significant turnover, rather than a static infection like murine TB. > > Host/Pathogen adaptation is not surprising to me. > I find it elegantly simple to understand that over time the host and > pathogen adjust to each other. How can that NOT happen if one is > infected for over 25 years as I was/am with Lyme? I think as the > host's immune system ages though, the pathogen eventually gets the > upper hand. I have had this though foremost in my mind as I devise > ways to ambush the buggers. I intend to keep the upper hand by hook > or by crook. > > Barb Quote Link to comment Share on other sites More sharing options...
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