Failure of Hyperimmune Gamma Globulin to Prevent Whooping Cough

Morris, David L.; McDonald, Jane

doi:10.1136/adc.32.163.236

“…Our results are also consistent with human clinical trials, where serum antibody titers could not be correlated with protection against B. pertussis [23,40,41]. The bacterial clearance time steps upon antibody treatment in the completely asynchronous model (Figure S3D) have a broader distribution but agree with the fundamental difference between the time scales of antibody-mediated clearance in B.…”

Section: Resultssupporting

confidence: 89%

Modeling Systems-Level Regulation of Host Immune Responses

Thakar

¹

,

Pilione

²

,

Kirimanjeswara

³

et al. 2007

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Many pathogens are able to manipulate the signaling pathways responsible for the generation of host immune responses. Here we examine and model a respiratory infection system in which disruption of host immune functions or of bacterial factors changes the dynamics of the infection. We synthesize the network of interactions between host immune components and two closely related bacteria in the genus Bordetellae. We incorporate existing experimental information on the timing of immune regulatory events into a discrete dynamic model, and verify the model by comparing the effects of simulated disruptions to the experimental outcome of knockout mutations. Our model indicates that the infection time course of both Bordetellae can be separated into three distinct phases based on the most active immune processes. We compare and discuss the effect of the species-specific virulence factors on disrupting the immune response during their infection of naive, antibody-treated, diseased, or convalescent hosts. Our model offers predictions regarding cytokine regulation, key immune components, and clearance of secondary infections; we experimentally validate two of these predictions. This type of modeling provides new insights into the virulence, pathogenesis, and host adaptation of disease-causing microorganisms and allows systems-level analysis that is not always possible using traditional methods.

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“…Adoptive transfer of convalescent-phase serum was sufficient to rapidly clear the lower respiratory tract of the broadhost-range pathogen B. bronchiseptica but not the human-specific pathogens B. pertussis and B. parapertussis. These results obtained with the mouse model are consistent with human clinical trials, in which serum antibody titers could not be correlated with protection against B. pertussis and intravenous immunoglobulin therapy had modest effects, thus supporting the validity of the mouse model as accurately reflecting the roles of individual host immune functions (3,11). Since B. pertussis and B. parapertussis appear to have emerged independently as human pathogens and each is more closely related to a B. bronchiseptica-like progenitor than each is to the other (16), these results raise the possibility that resistance to serum antibodies may relate to their adaptation to humans.…”

Section: Discussionsupporting

confidence: 74%

Role of Antibodies in Immunity to Bordetella Infections

Kirimanjeswara

¹

,

Mann

²

,

Harvill

³

2003

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The persistence of Bordetella pertussis and B. parapertussis within vaccinated populations and the reemergence of associated disease highlight the need to better understand protective immunity. The present study examined host immunity to bordetellae and addressed potential concerns about the mouse model by using a comparative approach including the closely related mouse pathogen B. bronchiseptica. As previously observed with B. pertussis, all three organisms persisted throughout the respiratory tracts of B-cell-deficient mice, indicating that B cells are required for bacterial clearance. However, adoptively transferred antibodies rapidly cleared B. bronchiseptica but not human pathogens. These results obtained with the mouse model are consistent with human clinical observations, including the lack of correlation between antibody titers and protection, as well as the limited efficacy of intravenous immunoglobulin treatments against human disease. Together, this evidence suggests that the mouse model accurately reflects substantial differences between immunities to these organisms. Although both B. pertussis and B. parapertussis are more closely related to B. bronchiseptica than they are to each other, they share the ability to resist rapid clearance from the lower respiratory tract by adoptively transferred antibodies, an adaptation that correlates with their emergence as human pathogens that circulate within vaccinated populations.Bordetella bronchiseptica, B. pertussis, and B. parapertussis are closely related gram-negative respiratory pathogens that have recently been reclassified as subspecies (12, 16). B. pertussis and B. parapertussis appear to have diverged independently from a B. bronchiseptica-like progenitor and are highly infectious pathogens that primarily infect humans, causing the acute and severe disease pertussis or whooping cough (5, 6). In contrast, B. bronchiseptica infects a wide range of mammals (4), typically asymptomatically, and persists in the upper respiratory tract indefinitely (4). The basis for the interspecies differences in host range and severity of disease is not known, but these differences may be related to differences between bacterial subspecies or host differences in physiology or immune response to Bordetella infection.Little is known definitively about the normal human immune response to Bordetella infection because it has generally been studied in individuals who were previously vaccinated (10). In the murine model, B cells are necessary to eliminate B. pertussis, suggesting that antibodies have a critical role in clearance (9). Although the importance of antibodies in immunity to other bacterial respiratory pathogens, such as Haemophilus influenzae and Pasteurella multocida, are well documented (10) and Bordetella-specific antibodies are generated in response to vaccination or infection (15), anti-Bordetella titers do not correlate well with protection in large clinical trials (3). In contrast to natural immunity following an infection, vaccination provides little, if any...

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“…In agreement with our model, experimental studies indicate that the adoptive transfer of serum antibodies results in the clearance of B. bronchiseptica by day 3 after inoculation, but B. pertussis is not cleared earlier [39]. Our results are also consistent with human clinical trials, where serum antibody titers could not be correlated with protection against B. pertussis [23,40,41]. The bacterial clearance time steps upon antibody treatment in the completely asynchronous model ( Figure S3D) have a broader distribution but agree with the fundamental difference between the time scales of antibody-mediated clearance in B. bronchiseptica and B. pertussis.…”

Section: Systemic Effects Of Deletions and Comparison With Experimentsupporting

confidence: 82%

Modeling Systems-Level Regulation of Host Immune Responses

Thakar¹,

Pilione²,

et al. 2005

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Many pathogens are able to manipulate the signaling pathways responsible for the generation of host immune responses. Here we examine and model a respiratory infection system in which disruption of host immune functions or of bacterial factors changes the dynamics of the infection. We synthesize the network of interactions between host immune components and two closely related bacteria in the genus Bordetellae. We incorporate existing experimental information on the timing of immune regulatory events into a discrete dynamic model, and verify the model by comparing the effects of simulated disruptions to the experimental outcome of knockout mutations. Our model indicates that the infection time course of both Bordetellae can be separated into three distinct phases based on the most active immune processes. We compare and discuss the effect of the species-specific virulence factors on disrupting the immune response during their infection of naive, antibody-treated, diseased, or convalescent hosts. Our model offers predictions regarding cytokine regulation, key immune components, and clearance of secondary infections; we experimentally validate two of these predictions. This type of modeling provides new insights into the virulence, pathogenesis, and host adaptation of disease-causing microorganisms and allows systems-level analysis that is not always possible using traditional methods.

show abstract

Failure of Hyperimmune Gamma Globulin to Prevent Whooping Cough

Cited by 42 publications

References 3 publications

Modeling Systems-Level Regulation of Host Immune Responses

Modeling Systems-Level Regulation of Host Immune Responses

Role of Antibodies in Immunity to Bordetella Infections

Modeling Systems-Level Regulation of Host Immune Responses

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