Immunity to Nontypeable Haemophilus influenzaeElucidating Protective Responses
University at Buffalo Buffalo, New York+, http://www.100md.com
Nontypeable (nonencapsulated) Haemophilus influenzae is present frequently in the lower airways of adults with chronic obstructive pulmonary disease (COPD) and bronchiectasis during clinically stable periods (1, 2). These bacteria are in a constant state of turnover, releasing potent inflammatory molecules contributing to airway inflammation. In addition to colonizing the lower airways during clinically stable periods, H. influenzae is the most common bacterial cause of exacerbations of COPD and bronchiectasis (1, 2). As a result, the bacterium has been the subject of increasingly intense investigation over the past decade. The acquisition and clearance of H. influenzae from the human respiratory tract is a dynamic, complex process involving multiple microbial adhesins whose expression is regulated, host responses to microbial antigens and both mucosal and systemic immune responses. Elucidating the elements of this complex interaction between host and pathogen will be important in the development of novel strategies to prevent colonization and/or infection by H. influenzae in adults with COPD and bronchiectasis.
In this issue of AJRCCM (pp. 587–592), King and coworkers (3) report important work characterizing the human immune response to antigens of H. influenzae in adults with bronchiectasis who experienced recurrent H. influenzae infections. The observation that the immune response in adults with bronchiectasis differs from that of healthy adults raises interesting speculations regarding the role of immune responses in the pathogenesis of infection in bronchiectasis and in determining the elements of a potentially protective immune response to H. influenzae. King and coworkers (3) showed that the distribution of serum IgG subclasses to H. influenzae antigens differed between adults with bronchiectasis and healthy controls. In addition, they showed that the immune response to H. influenzae antigens in adults with bronchiectasis had characteristics suggesting a predominantly type 2 T helper cell response compared with healthy adults whose immune response was more characteristic of a type 1 T helper cell response. While the distinction between type 1 and type 2 responses is somewhat arbitrary, a type 1 response is the predominant response to intracellular pathogens, and a type 2 response is the predominant response to extracellular pathogens.
H. influenzae has long been considered an extracellular pathogen based on its binding to mucin and adherence to epithelial cells. Several lines of evidence, however, now establish that H. influenzae has both an extracellular and an intracellular niche in the human respiratory tract (4–9). Therefore, H. influenzae is present in the airway lumen, bound to mucin, adherent to respiratory epithelial cells, within the interstitium of the submucosa, and within cells of the respiratory tract. The novel observation of King and coworkers (3) that healthy adults who do not experience recurrent infections have a predominant type 1 response to H. influenzae antigens, and adults with bronchiectasis who experience recurrent infections make a predominantly type 2 response raises the speculation that a type 1 response is associated with relative protection from colonization or infection. If so, modulation of the immune response might be used to induce protection. This is an important area for investigation.
A hallmark of H. influenzae infections in bronchiectasis and COPD is their propensity for recurrence. Studies in animal models, in adults with COPD, and in children with otitis media all demonstrate that the most prominent antibody response is directed at strain specific determinants (10–15). The strain specificity of the immune response accounts at least in part for the recurrent nature of infections by H. influenzae, highlighting the importance of using antigens from the homologous infecting strain of H. influenzae to perform immunoasays. A limitation of the study of King and coworkers (3) is that strain specific immune responses were not detected because the antigen used in immunoassays was a heat inactivated, sonicated mixture of nine isolates of H. influenzae. This antigen preparation does not contain strain specific determinants known to be the target of human immune responses to H. influenzae. Moreover, these preparations contain varying concentrations of antigens expressed at different levels by different strains, adding the confounding variable of antigen concentration. The observation that differences between the bronchiectasis and healthy groups were observed using heterologous antigens suggests that even larger differences would be observed with homologous antigens because the most important immune responses with regard to protection may be directed at strain specific antigens.
The work by King and colleagues (3) shows that nontypeable H. influenzae induces a systemic antibody response and a cell-mediated immune response. Perhaps the most important question raised is what the immune responses detected by King and coworkers (3) actually mean. Do the responses simply represent a marker for repeated exposure to H. influenzae? Alternatively, will these immune responses teach us about the elements of a protective host response? Observing the effect of the immune responses detected by King and coworkers on the pattern of infection and colonization in longitudinal studies of adults with bronchiectasis and COPD will lead to important information about protective immunity to H. influenzae. The possibility that the cell-mediated immune response observed by King and coworkers is protective is consistent with the observation that the ability of T cells to recognize outer membrane protein P6 of H. influenzae is associated with relative protection from exacerbations of COPD (16). Little work has been performed on the mucosal immune response to H. influenzae in humans and this will be an important area for further study because the bacterium is a mucosal pathogen.
Elucidating the elements of an immune response that would prevent colonization or infection by new strains of H. influenzae would represent an effective guide to vaccine development by identifying a correlate of protection. A vaccine capable of preventing infection caused by nontypeable H. influenzae would have an enormous impact on patients with bronchiectasis and COPD by reducing mortality, morbidity, and health care costs. Elucidating the elements of a protective immune response to H. influenzae will be critical to achieve this goal.m(@p1cd, http://www.100md.com
REFERENCESm(@p1cd, http://www.100md.com
Sethi S, Murphy TF. Bacterial infection in chronic obstructive pulmonary disease in 2000. A state of the art review. Clin Microbiol Rev 2001;14:336–363.m(@p1cd, http://www.100md.com
Barker AF. Bronchiectasis. N Engl J Med 2002;346:1383–1393.m(@p1cd, http://www.100md.com
King PT, Hutchinson PE, Johnson PD, Holmes PW, Freezer NJ, Holdsworth SR. Adaptive immunity to nontypeable Haemophilus influenzae. Am J Respir Crit Care Med 2003;167:587–592.
Ketterer MR, Shao JQ, Hornick DB, Buscher B, Bandi VK, Apicella MA. Infection of primary human bronchial epithelial cells by Haemophilus influenzae: macropinocytosis as a mechanism of airway epithelial cell entry. Infect Immun 1999;67:4161–4170.:]z/|7c, http://www.100md.com
Moller LVM, Timens W, van der Bij W, Kooi K, de Wever B, Dankert J, Van Alphen L. Haemophilus influenzae in lung explants of patients with end-stage pulmonary disease. Am J Respir Crit Care Med 1998;157:950–956.:]z/|7c, http://www.100md.com
van Schilfgaarde M, Eijk P, Regelink A, van Ulsen P, Everts V, Dankert J, Van Alphen L. Haemophilus influenzae localized in epithelial cell layers is shielded from antibiotics and antibody-mediated bactericidal activity. Microb Pathog 1999;26:249–262.:]z/|7c, http://www.100md.com
Forsgren J, Samuelson A, Ahlin A, Jonasson J, Rynnel-Dagoo B, Lindberg A. Haemophilus influenzae resides and multiplies intracellularly in human adenoid tissue as demonstrated by in situ hybridization and bacterial viability assay. Infect Immun 1994;62:673–679.:]z/|7c, http://www.100md.com
Forsgren J, Samuelson A, Borrelli S, Christensson B, Jonasson J, Lindberg AA. Persistence of nontypeable Haemophilus influenzae in adenoid macrophages: a putative colonization mechanism. Acta Otolaryngol 1996;116:766–773.
Bandi V, Apicella MA, Mason E, Murphy TF, Siddiqi A, Atmar RL, Greenberg SB. Nontypeable Haemophilus influenzae in the lower respiratory tract of patients with chronic bronchitis. Am J Respir Crit Care Med 2001;164:2114–2119.:*p3, http://www.100md.com
Yi K, Murphy TF. Importance of an immunodominant surface-exposed loop on outer membrane protein P2 of nontypeable Haemophilus influenzae. Infect Immun. 1997;65:150–155.:*p3, http://www.100md.com
Yi K, Sethi S, Murphy TF. Human immune response to nontypeable Haemophilus influenzae in chronic bronchitis. J Infect Dis 1997;176:1247–1252.:*p3, http://www.100md.com
Duim B, Vogel L, Puijk W, Jansen HM, Meloen RH, Dankert J, Van Alphen L. Fine mapping of outer membrane protein P2 antigenic sites which vary during persistent infection by Haemophilus influenzae. Infect Immun 1996;64:4673–4679.:*p3, http://www.100md.com
Groeneveld K, Van Alphen L, Voorter C, Eijk PP, Jansen HM, Zanen HC. Antigenic drift of Haemophilus influenzae in patients with chronic obstructive pulmonary disease. Infect Immun 1989;57:3038–3044.:*p3, http://www.100md.com
Van Alphen L, Eijk P, Geelen-van den Broek L, Dankert J. Immunochemical characterization of variable epitopes of outer membrane protein P2 of nontypeable Haemophilus influenzae. Infect Immun 1991;59:247–252.:*p3, http://www.100md.com
Faden H, Bernstein J, Brodsky L, Stanievich J, Krystofik D, Shuff C, Hong JJ, Ogra PL. Otitis media in children. I. The systemic immune response tonontypable Haemophilus influenzae. J Infect Dis 1989;160:999–1004.:*p3, http://www.100md.com
Abe Y, Murphy TF, Sethi S, Faden HS, Dmochowski J, Harabuchi Y, Thanavala YM. Lymphocyte proliferative response to P6 of Haemophilus influenzae is associated with relative protection from exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;165:967–971.(Timothy F. Murphy, M.D.)
Nontypeable (nonencapsulated) Haemophilus influenzae is present frequently in the lower airways of adults with chronic obstructive pulmonary disease (COPD) and bronchiectasis during clinically stable periods (1, 2). These bacteria are in a constant state of turnover, releasing potent inflammatory molecules contributing to airway inflammation. In addition to colonizing the lower airways during clinically stable periods, H. influenzae is the most common bacterial cause of exacerbations of COPD and bronchiectasis (1, 2). As a result, the bacterium has been the subject of increasingly intense investigation over the past decade. The acquisition and clearance of H. influenzae from the human respiratory tract is a dynamic, complex process involving multiple microbial adhesins whose expression is regulated, host responses to microbial antigens and both mucosal and systemic immune responses. Elucidating the elements of this complex interaction between host and pathogen will be important in the development of novel strategies to prevent colonization and/or infection by H. influenzae in adults with COPD and bronchiectasis.
In this issue of AJRCCM (pp. 587–592), King and coworkers (3) report important work characterizing the human immune response to antigens of H. influenzae in adults with bronchiectasis who experienced recurrent H. influenzae infections. The observation that the immune response in adults with bronchiectasis differs from that of healthy adults raises interesting speculations regarding the role of immune responses in the pathogenesis of infection in bronchiectasis and in determining the elements of a potentially protective immune response to H. influenzae. King and coworkers (3) showed that the distribution of serum IgG subclasses to H. influenzae antigens differed between adults with bronchiectasis and healthy controls. In addition, they showed that the immune response to H. influenzae antigens in adults with bronchiectasis had characteristics suggesting a predominantly type 2 T helper cell response compared with healthy adults whose immune response was more characteristic of a type 1 T helper cell response. While the distinction between type 1 and type 2 responses is somewhat arbitrary, a type 1 response is the predominant response to intracellular pathogens, and a type 2 response is the predominant response to extracellular pathogens.
H. influenzae has long been considered an extracellular pathogen based on its binding to mucin and adherence to epithelial cells. Several lines of evidence, however, now establish that H. influenzae has both an extracellular and an intracellular niche in the human respiratory tract (4–9). Therefore, H. influenzae is present in the airway lumen, bound to mucin, adherent to respiratory epithelial cells, within the interstitium of the submucosa, and within cells of the respiratory tract. The novel observation of King and coworkers (3) that healthy adults who do not experience recurrent infections have a predominant type 1 response to H. influenzae antigens, and adults with bronchiectasis who experience recurrent infections make a predominantly type 2 response raises the speculation that a type 1 response is associated with relative protection from colonization or infection. If so, modulation of the immune response might be used to induce protection. This is an important area for investigation.
A hallmark of H. influenzae infections in bronchiectasis and COPD is their propensity for recurrence. Studies in animal models, in adults with COPD, and in children with otitis media all demonstrate that the most prominent antibody response is directed at strain specific determinants (10–15). The strain specificity of the immune response accounts at least in part for the recurrent nature of infections by H. influenzae, highlighting the importance of using antigens from the homologous infecting strain of H. influenzae to perform immunoasays. A limitation of the study of King and coworkers (3) is that strain specific immune responses were not detected because the antigen used in immunoassays was a heat inactivated, sonicated mixture of nine isolates of H. influenzae. This antigen preparation does not contain strain specific determinants known to be the target of human immune responses to H. influenzae. Moreover, these preparations contain varying concentrations of antigens expressed at different levels by different strains, adding the confounding variable of antigen concentration. The observation that differences between the bronchiectasis and healthy groups were observed using heterologous antigens suggests that even larger differences would be observed with homologous antigens because the most important immune responses with regard to protection may be directed at strain specific antigens.
The work by King and colleagues (3) shows that nontypeable H. influenzae induces a systemic antibody response and a cell-mediated immune response. Perhaps the most important question raised is what the immune responses detected by King and coworkers (3) actually mean. Do the responses simply represent a marker for repeated exposure to H. influenzae? Alternatively, will these immune responses teach us about the elements of a protective host response? Observing the effect of the immune responses detected by King and coworkers on the pattern of infection and colonization in longitudinal studies of adults with bronchiectasis and COPD will lead to important information about protective immunity to H. influenzae. The possibility that the cell-mediated immune response observed by King and coworkers is protective is consistent with the observation that the ability of T cells to recognize outer membrane protein P6 of H. influenzae is associated with relative protection from exacerbations of COPD (16). Little work has been performed on the mucosal immune response to H. influenzae in humans and this will be an important area for further study because the bacterium is a mucosal pathogen.
Elucidating the elements of an immune response that would prevent colonization or infection by new strains of H. influenzae would represent an effective guide to vaccine development by identifying a correlate of protection. A vaccine capable of preventing infection caused by nontypeable H. influenzae would have an enormous impact on patients with bronchiectasis and COPD by reducing mortality, morbidity, and health care costs. Elucidating the elements of a protective immune response to H. influenzae will be critical to achieve this goal.m(@p1cd, http://www.100md.com
REFERENCESm(@p1cd, http://www.100md.com
Sethi S, Murphy TF. Bacterial infection in chronic obstructive pulmonary disease in 2000. A state of the art review. Clin Microbiol Rev 2001;14:336–363.m(@p1cd, http://www.100md.com
Barker AF. Bronchiectasis. N Engl J Med 2002;346:1383–1393.m(@p1cd, http://www.100md.com
King PT, Hutchinson PE, Johnson PD, Holmes PW, Freezer NJ, Holdsworth SR. Adaptive immunity to nontypeable Haemophilus influenzae. Am J Respir Crit Care Med 2003;167:587–592.
Ketterer MR, Shao JQ, Hornick DB, Buscher B, Bandi VK, Apicella MA. Infection of primary human bronchial epithelial cells by Haemophilus influenzae: macropinocytosis as a mechanism of airway epithelial cell entry. Infect Immun 1999;67:4161–4170.:]z/|7c, http://www.100md.com
Moller LVM, Timens W, van der Bij W, Kooi K, de Wever B, Dankert J, Van Alphen L. Haemophilus influenzae in lung explants of patients with end-stage pulmonary disease. Am J Respir Crit Care Med 1998;157:950–956.:]z/|7c, http://www.100md.com
van Schilfgaarde M, Eijk P, Regelink A, van Ulsen P, Everts V, Dankert J, Van Alphen L. Haemophilus influenzae localized in epithelial cell layers is shielded from antibiotics and antibody-mediated bactericidal activity. Microb Pathog 1999;26:249–262.:]z/|7c, http://www.100md.com
Forsgren J, Samuelson A, Ahlin A, Jonasson J, Rynnel-Dagoo B, Lindberg A. Haemophilus influenzae resides and multiplies intracellularly in human adenoid tissue as demonstrated by in situ hybridization and bacterial viability assay. Infect Immun 1994;62:673–679.:]z/|7c, http://www.100md.com
Forsgren J, Samuelson A, Borrelli S, Christensson B, Jonasson J, Lindberg AA. Persistence of nontypeable Haemophilus influenzae in adenoid macrophages: a putative colonization mechanism. Acta Otolaryngol 1996;116:766–773.
Bandi V, Apicella MA, Mason E, Murphy TF, Siddiqi A, Atmar RL, Greenberg SB. Nontypeable Haemophilus influenzae in the lower respiratory tract of patients with chronic bronchitis. Am J Respir Crit Care Med 2001;164:2114–2119.:*p3, http://www.100md.com
Yi K, Murphy TF. Importance of an immunodominant surface-exposed loop on outer membrane protein P2 of nontypeable Haemophilus influenzae. Infect Immun. 1997;65:150–155.:*p3, http://www.100md.com
Yi K, Sethi S, Murphy TF. Human immune response to nontypeable Haemophilus influenzae in chronic bronchitis. J Infect Dis 1997;176:1247–1252.:*p3, http://www.100md.com
Duim B, Vogel L, Puijk W, Jansen HM, Meloen RH, Dankert J, Van Alphen L. Fine mapping of outer membrane protein P2 antigenic sites which vary during persistent infection by Haemophilus influenzae. Infect Immun 1996;64:4673–4679.:*p3, http://www.100md.com
Groeneveld K, Van Alphen L, Voorter C, Eijk PP, Jansen HM, Zanen HC. Antigenic drift of Haemophilus influenzae in patients with chronic obstructive pulmonary disease. Infect Immun 1989;57:3038–3044.:*p3, http://www.100md.com
Van Alphen L, Eijk P, Geelen-van den Broek L, Dankert J. Immunochemical characterization of variable epitopes of outer membrane protein P2 of nontypeable Haemophilus influenzae. Infect Immun 1991;59:247–252.:*p3, http://www.100md.com
Faden H, Bernstein J, Brodsky L, Stanievich J, Krystofik D, Shuff C, Hong JJ, Ogra PL. Otitis media in children. I. The systemic immune response tonontypable Haemophilus influenzae. J Infect Dis 1989;160:999–1004.:*p3, http://www.100md.com
Abe Y, Murphy TF, Sethi S, Faden HS, Dmochowski J, Harabuchi Y, Thanavala YM. Lymphocyte proliferative response to P6 of Haemophilus influenzae is associated with relative protection from exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;165:967–971.(Timothy F. Murphy, M.D.)