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For whom the bug tolls
News & Comment
TRENDS in Microbiology Vol.9 No.3 March 2001
109
Sensitization to sand fly bite prevents cutaneous leishmaniasis Until recently, from both epidemiological and clinical perspectives, arthropods have been considered as little more than delivery systems for the pathogens that they carry. However, insofar as components of their saliva have been shown to modify the outcome of infection, an active modulation by arthropod vectors of disease transmission is starting to gain recognition. The disease most studied in this context is cutaneous leishmaniasis, which is transmitted exclusively by the bite of infectious sand flies. Kamhawi et al.1 have now described a reproducible murine model of Leishmania major infection transmitted by its natural vector, Phlebotomus papatasi, in which the ear is the site of parasite inoculation. The respective lesion-healing and lesion-nonhealing phenotypes of C57BL/6 and BALB/c mice that have proved a powerful tool for dissection of the T helper type 1 (Th1)/Th2
immunological paradigm, established using high-dose needle inocula, were maintained in fly-transmitted infections. It is demonstrated that prior exposure of mice to bites of uninfected sand flies alone provides a significant degree of protection against L. major, sufficient to confer resistance to subsequent biting by infected sand flies. For both BALB/c and C57BL/6 mice, prior exposure to P. papatasi bites resulted in a striking reduction in both the severity of dermal lesions and the parasite load. The protective mechanism involves a strong delayed-type hypersensitivity reaction and production of interleukin (IL)-12 and interferon (IFN)-γ at the bite site. The rapidly raised secretion of these cytokines might activate infected macrophages for killing while the infection is initially establishing and might also promote an early polarized Leishmania-specific Th1-type response that is the immunological hallmark of a healing
infection. The molecular identity of the stimulus that triggers this protective response remains to be elucidated but is thought to be a component of Phlebotomus saliva. These findings are very relevant to leishmaniasis of humans, for which many individuals in endemic regions are exposed to the bites of Leishmania-free sand flies before receiving an infective bite. Thus, a person’s exposure history to uninfected phlebotomines could influence their susceptibility to, and the severity of, infection. Moreover, salivary antigens might be effective components of vaccines against this and other vector-borne infectious diseases. 1 Kamhawi, S. et al. (2000) Protection against cutaneous leishmaniasis resulting from bites of uninfected sand flies. Science 290, 1351–1354
Andrew Taylor-Robinson [email protected]
For whom the bug tolls Toll-like receptors (TLRs) belong to a family of conserved mediators of the innate immune response and recognize specific molecular patterns on microbial pathogens: TLR2 mediates the response to microbial lipoproteins and TLR4 is required for the response to lipopolysaccharide (LPS). Hemmi et al.1 have now identified TLR9 by its sequence similarity to known TLRs. The authors isolated the mouse and human TLR9 genes and a TLR9-deficient mouse was generated. Although cells from the TLR9-deficient mouse showed normal responses to lipoproteins and LPS, they were defective in their response to the unmethylated oligodeoxynucleotide sequence CpG. This sequence is found much more commonly in bacterial DNA than in mammalian DNA and is responsible for the stimulatory effects of bacterial DNA on mammalian immune cells. Compared with cells from wild-type mice, those from the TLR9-deficient mice did not respond to CpG. In particular, splenocytes did not proliferate, induction of increased MHC class II expression was not observed on B cells, macrophages did not produce detectable levels of inflammatory cytokines or specific signal
transduction events, and dendritic cells did not produce detectable levels of interleukin (IL-12). To determine whether this lack of response was mirrored in vivo, wild-type and TLR9-deficient mice were treated with D-galactosamine and CpG, conditions known to induce lethal shock. Wild-type mice died within 12 hours of this treatment, whereas the TLR9-deficient mice were highly resistant to this CpGinduced shock syndrome. The in vivo administration of CpG has also been shown to induce a Th1-biased immune response; this was not observed in the TLR9-deficient mice. Together, these results indicate that the cellular response to the CpG oligodeoxynucleotide is mediated by TLR9. The human and mouse TLR9 proteins share 75.5% amino acid identity, a finding that might explain why slightly different CpG sequences optimally activate human and mouse immune cells. Besides allowing for a better understanding of innate immunity, deciphering the mechanism that allows mammalian cells to respond specifically to bacterial DNA and not to mammalian DNA will provide a basis for the selection of specific nucleotide
sequences to act as better adjuvants in DNA vaccines. 1 Hemmi, H. et al. (2000) A Toll-like receptor recognized bacterial DNA. Nature 408, 740–745
Joanna Goldberg [email protected]
What does the human genome sequence mean to you? For a thorough and independent analysis of the meaning and importance of the February publications of the draft human genome sequences, visit http://news.bmn.com/hmsbeagle/96 /notes/feature3. To mark the importance of the event, we are prepublishing a number of Trends articles on these publications in our free, online magazine, HMS Beagle. You can’t afford to miss these up-tothe-minute commentaries, opinions and updates, written by leading players from across the whole of biology. And they’re free!
http://tim.trends.com 0966-842X/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
TRENDS in Microbiology Vol.9 No.3 March 2001
109
Sensitization to sand fly bite prevents cutaneous leishmaniasis Until recently, from both epidemiological and clinical perspectives, arthropods have been considered as little more than delivery systems for the pathogens that they carry. However, insofar as components of their saliva have been shown to modify the outcome of infection, an active modulation by arthropod vectors of disease transmission is starting to gain recognition. The disease most studied in this context is cutaneous leishmaniasis, which is transmitted exclusively by the bite of infectious sand flies. Kamhawi et al.1 have now described a reproducible murine model of Leishmania major infection transmitted by its natural vector, Phlebotomus papatasi, in which the ear is the site of parasite inoculation. The respective lesion-healing and lesion-nonhealing phenotypes of C57BL/6 and BALB/c mice that have proved a powerful tool for dissection of the T helper type 1 (Th1)/Th2
immunological paradigm, established using high-dose needle inocula, were maintained in fly-transmitted infections. It is demonstrated that prior exposure of mice to bites of uninfected sand flies alone provides a significant degree of protection against L. major, sufficient to confer resistance to subsequent biting by infected sand flies. For both BALB/c and C57BL/6 mice, prior exposure to P. papatasi bites resulted in a striking reduction in both the severity of dermal lesions and the parasite load. The protective mechanism involves a strong delayed-type hypersensitivity reaction and production of interleukin (IL)-12 and interferon (IFN)-γ at the bite site. The rapidly raised secretion of these cytokines might activate infected macrophages for killing while the infection is initially establishing and might also promote an early polarized Leishmania-specific Th1-type response that is the immunological hallmark of a healing
infection. The molecular identity of the stimulus that triggers this protective response remains to be elucidated but is thought to be a component of Phlebotomus saliva. These findings are very relevant to leishmaniasis of humans, for which many individuals in endemic regions are exposed to the bites of Leishmania-free sand flies before receiving an infective bite. Thus, a person’s exposure history to uninfected phlebotomines could influence their susceptibility to, and the severity of, infection. Moreover, salivary antigens might be effective components of vaccines against this and other vector-borne infectious diseases. 1 Kamhawi, S. et al. (2000) Protection against cutaneous leishmaniasis resulting from bites of uninfected sand flies. Science 290, 1351–1354
Andrew Taylor-Robinson [email protected]
For whom the bug tolls Toll-like receptors (TLRs) belong to a family of conserved mediators of the innate immune response and recognize specific molecular patterns on microbial pathogens: TLR2 mediates the response to microbial lipoproteins and TLR4 is required for the response to lipopolysaccharide (LPS). Hemmi et al.1 have now identified TLR9 by its sequence similarity to known TLRs. The authors isolated the mouse and human TLR9 genes and a TLR9-deficient mouse was generated. Although cells from the TLR9-deficient mouse showed normal responses to lipoproteins and LPS, they were defective in their response to the unmethylated oligodeoxynucleotide sequence CpG. This sequence is found much more commonly in bacterial DNA than in mammalian DNA and is responsible for the stimulatory effects of bacterial DNA on mammalian immune cells. Compared with cells from wild-type mice, those from the TLR9-deficient mice did not respond to CpG. In particular, splenocytes did not proliferate, induction of increased MHC class II expression was not observed on B cells, macrophages did not produce detectable levels of inflammatory cytokines or specific signal
transduction events, and dendritic cells did not produce detectable levels of interleukin (IL-12). To determine whether this lack of response was mirrored in vivo, wild-type and TLR9-deficient mice were treated with D-galactosamine and CpG, conditions known to induce lethal shock. Wild-type mice died within 12 hours of this treatment, whereas the TLR9-deficient mice were highly resistant to this CpGinduced shock syndrome. The in vivo administration of CpG has also been shown to induce a Th1-biased immune response; this was not observed in the TLR9-deficient mice. Together, these results indicate that the cellular response to the CpG oligodeoxynucleotide is mediated by TLR9. The human and mouse TLR9 proteins share 75.5% amino acid identity, a finding that might explain why slightly different CpG sequences optimally activate human and mouse immune cells. Besides allowing for a better understanding of innate immunity, deciphering the mechanism that allows mammalian cells to respond specifically to bacterial DNA and not to mammalian DNA will provide a basis for the selection of specific nucleotide
sequences to act as better adjuvants in DNA vaccines. 1 Hemmi, H. et al. (2000) A Toll-like receptor recognized bacterial DNA. Nature 408, 740–745
Joanna Goldberg [email protected]
What does the human genome sequence mean to you? For a thorough and independent analysis of the meaning and importance of the February publications of the draft human genome sequences, visit http://news.bmn.com/hmsbeagle/96 /notes/feature3. To mark the importance of the event, we are prepublishing a number of Trends articles on these publications in our free, online magazine, HMS Beagle. You can’t afford to miss these up-tothe-minute commentaries, opinions and updates, written by leading players from across the whole of biology. And they’re free!
http://tim.trends.com 0966-842X/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.