A Non-Human Primate Model of Acute Group A Streptococcus Pharyngitis - Bacterial Pathogenesis: Methods and Protocols - page 241

preventable pediatric heart disease in developing countries (1,4) . In aggregate,
GAS infections result in an estimated 500,000 deaths worldwide per year,
clearly defining GAS as a major public health concern (4) . The mortality,
morbidity, and financial burden associated with GAS infections emphasize the
critical need for a more detailed understanding of the complex strategies used
by this pathogen to successfully circumvent host immune defenses and cause
disease.
GAS pathogenesis studies have been hampered by the absence of animal
models of disease that recapitulate human infections. Although mouse models
of infection are currently most frequently used, a debate about the relevance
of these models with regard to the human host remains (6,7) . Following the
reasoning that humans and non-human primates are closely related phylo-
genetically, several non-human primate models of GAS diseases have been
developed over the last 100 years. One of the earliest studies using a non-
human primate model to study streptococcal disease was published in 1907 by
Beattie, who observed clinical manifestations reminiscent of rheumatic fever in
infected monkeys (8) . About a decade later, Blake et al. published work in which
intratracheal injections of GAS were used to study pneumonia in non-human
primates (9) . In 1946, Watson observed that intranasal challenge of monkeys
with GAS led to serotype-specific immunity to this organism (10) . In 1976,
Köhler et al. reported the protective effect of M protein in an immunization
study using rhesus monkeys (11) . Since then, several reports describe
non-human primate models used to study invasive GAS diseases (12,13) .
The most commonly used animal model to study GAS pharyngitis is the mouse
upper respiratory tract infectionmodel (14,15,16) . However, mice do not develop
a true pharyngitis and only a relatively few animals become colonized even when
high concentrations of inocula are used. Moreover, in our experience the data
obtained with this model are poorly reproducible, and because the blood volume
of the mouse is small the ability to easily perform many standard immunologic
assays is limited. In addition, several gas virulence factor do not act on mouse
molecules. Therefore, the relevance, significance, and usefulness of the murine
model of GAS pharyngitis is limited. Several independent studies indicate that
non-human primates may provide a more suitable model to study GAS pharyn-
gitis: animals are successfully colonized by GAS, and limited data indicate that
the infections mimicked the humoral immune response characteristic for human
disease (10,17,18,19,20) .
The inadequacies of the mouse model of infection led us to develop a non-
human primate model of GAS pharyngitis that is a superb phenocopy of human
infection and has become the gold-standard model for studying GAS-host
molecular interactions in the upper respiratory tract (21,22,23,24) .