Joel D. Ernst

Immune responses in tuberculosis.

The initial interaction of Mycobacterium tuberculosis with phagocytes through Toll-like receptors can affect induction of the adaptive response by inflammatory cytokine production, as well as begin the process of bacterial containment by induction of antimycobacterial functions. Advances in T cell research in tuberculosis include identification of antigens recognized by CD8(+) T cells in infected hosts, elucidation of antimycobacterial mechanisms of T cells and the discovery of CD8(+) T cells that recognize antigens presented by a variety of non-classical molecules.

Bacterial inhibition of phagocytosis.

The concerted study of molecular mechanisms of phagocytosis and the inhibition of phagocytosis by specific products of extracellular bacterial pathogens has borne considerable fruit. The importance of tyrosine phosphorylation and of the Rho family of GTPases has become clear to cell biologists, but pathogenic bacteria recognized the importance of these signalling pathways in phagocytic cells long ago. The discoveries described in this review are only the beginning. The simultaneous pursuit of the mechanisms and molecules involved in the initiation and regulation of phagocytosis and that pathogenic bacteria use to inhibit phagocytosis will surely identify more interesting pathways on each side of the contest. Are there any obvious possibilities? There are several bacterial factors that have the potential to inhibit known mechanisms of phagocytosis. Clostridium species, for example, make a number of exotoxins of interest. Clostridium botulinum and Clostridium tetani neurotoxins inactivate the regulated secretory machinery by proteolytic cleavage of SNARE proteins, and targets of tetanus toxin and botulinum b toxin inhibit the exocytotic delivery of membrane vesicles needed for phagocytosis of large particles (Hackam et al., 1998). Moreover, the C3 exotoxin of C. botulinum catalyses ADP ribosylation and inactivation of rho family GTPases (Wiegers et al., 1991), and toxins A and B of C. difficile UDP-glucosylate and inactivate rho GTPases and thereby disrupt the actin cytoskeleton (Just et al., 1995a,b). However, as Clostridia lack the machinery for type III secretion, these proteins are not rapidly targeted to the phagocyte cytoplasm. More searching may reveal a pathogen that has combined the type III secretory machinery with clostridia toxin-like substrates. A potentially unique strategy for remaining outside phagocytes is exhibited by Helicobacter pylori, which contain a type IV secretion system. Unopsonized virulent strains of H. pylori bind readily to macrophages but are only internalized after a delay of several minutes. Such a delay appears to be sufficient for the bacteria to remain extracellular (Allen et al., 2000). Elucidation of the mechanism used by H. pylori to delay phagocytosis may reveal one or more novel virulence factors as well as one or more novel targets in the phagocyte that will add to the understanding of a fundamental process in host defence. Another field ripe for further mechanistic investigation is complement receptor-mediated phagocytosis. Dedicated study of the molecular events and molecular mediators of phagocytosis downstream of CR3 is likely to reveal interesting differences from FcgammaR phagocytosis and is just as likely to reveal that microbes have discovered unique mechanisms for circumventing them. Study of extracellular pathogens and the mechanisms that they use to remain outside phagocytic cells has revealed a great deal about the initial encounter between pathogen and phagocyte. We can look forward to additional discoveries about the host-pathogen interactions and the mechanisms and factors that each side uses to battle against the other.

Phagocytosis of bacteria and bacterial pathogenicity

1. Introduction Olle Stendahl 2. Phagocytosis: receptors and biology Wouter L. W. Hazenbos and Eric J. Brown 3. Receptor-initiated signal transduction during phagocytosis Kassidy K. Huynh and Sergio Grinstein 4. Life, death, and inflammation: manipulation of phagocyte function by Helicobacter pylori Lee-Ann H. Allen 5. Phagocytosis of Streptococcus pneumoniae Dominic L. Jack, David H. Dockrell, Stephen B. Gordon and Robert C. Read 6. Yersinia inhibition of phagocytosis Maria Fallman and Anna Gustavsson 7. Listeria invasion and spread in nonprofessional phagocytes Frederick S. Southwick 8. Mycobacterium tuberculosis: mechanisms of phagocytosis and intracellular survival Joel D. Ernst and Andrea Wolf.

Use of a novel strategy for the preparation and characterization of an antipeptide antibody capable of recognizing members of the annexin family

Annexins are structurally-related proteins which bind phospholipids in a Ca2+-dependent manner. We have used a novel coupling strategy to prepare an antiserum directed against a 17-amino acid synthetic peptide that resembles the sequence of a highly-conserved portion of these proteins. This antipeptide serum specifically recognizes 5 of 6 human annexins on Western blots, despite differences between the protein and peptide sequences of 3 or 4 amino acids. The antiserum does not recognize endonexin II, whose sequence differs from that of the peptide by 6 amino acids. The availability of multiple proteins with known amino acid sequence has allowed analysis of structural requirements for recognition by this antibody. In some situations, use of such an antibody may allow the identification of a protein as a member of a family.

Editorial Response: Variation in Clinical and Immune Responses to Bacille Calmette-Guérin-Implications for an Improved Tuberculosis Vaccine

Renewed concern about the worldwide problem of tubercu- BCG 1 month after inoculation (one was still shedding viable losis has stimulated efforts to define mechanisms that allow BCG 2 months after inoculation). This finding prompts a cauMycobacterium tuberculosis unequaled success as a pathogen, tionary note from the investigators that shedding of viable BCG to identify new drug targets, and to develop an improved vac- may present a hazard to contacts with AIDS, with an attendant cine. In this issue of Clinical Infectious Diseases, Hoft and risk of disseminated BCG infection in the contacts. colleagues [1] report results of their efforts to characterize the Second, the investigators found some interesting correlations response to the existing tuberculosis vaccine, BCG. Despite with the duration of vaccine-induced ulceration. Subjects with widespread use of the BCG vaccine, its effects are not well the highest in vitro lymphoproliferative response to M. tubercuunderstood, controlled clinical trials have yielded variable re- losis antigens before vaccination had the shortest duration of sults, and it has not prevented tuberculosis from causing the ulceration. This finding illustrates that before vaccination, death of more humans each year than any other single infection. healthy volunteers with negative PPD skin tests differ in their responses detected by assays that are generally taken to reflect specific acquired cellular immunity. It is interesting to speculate

Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design

Tuberculosis (TB) is a large global health problem, in part because of the long period of coevolution of the pathogen, Mycobacterium tuberculosis, and its human host. A major factor that sustains the global epidemic of TB is the lack of a sufficiently effective vaccine. While basic mechanisms of immunity that protect against TB have been identified, attempts to improve immunity to TB by vaccination have been disappointing. This Review discusses the mechanisms used by M.xa0tuberculosis to evade innate and adaptive immunity and that likely limit the efficacy of vaccines developed to date. Despite multiple mechanisms of immune evasion, recent trials have indicated that effective TB vaccines remain an attainable goal. This Review discusses how knowledge from other systems can inform improvements on current vaccine approaches.