PROJECT SUMMARY
Nocardiosis is a severe infectious disease caused by the gram-positive bacteria Nocardia spp. Although
exposure to the pathogen is universal, only a small fraction of exposed individuals develop severe disease. The
observation that the epidemic (HIV infection) and iatrogenic (T cell immunosuppression) forms of nocardiosis
are due to acquired immunodeficiency suggests that nocardiosis in otherwise healthy individuals may be due to
inherited immunodeficiency. Further strengthening this point, patients with some primary immunodeficiencies
(PIDs) such as chronic granulomatous disease (CGD)1–5, severe combined immunodeficiency (SCID)6, or
hypogammaglobulinemia 7,8 develop nocardiosis. Hence, we hypothesize that nocardiosis in otherwise healthy
individuals is an undiagnosed PID. We have recruited a growing cohort of patients without any detectable risk
factors that develop severe nocardiosis to test this hypothesis. Furthermore, we have performed whole-exome
sequencing (WES) in these patients and found that all the genes described to cause a PID are wild type
suggesting that inborn errors of immunity in additional genes may account for nocardiosis in some of these
patients. Interestingly, we have found that one-fifth of our patients carry neutralizing anti-GM-CSF auto-
antibodies confirming that exposure to Nocardia spp. is necessary. Still, a permissive immune state of the host
is required to develop the diseases. Therefore, this proposal aims to understand the genetic and immunological
components of nocardiosis by using two complementary approaches. In our first specific aim, we will use a
systems immunology approach to identify immunological abnormalities in the patients, such as the presence of
auto-antibodies against cytokines, antibody deficiencies, or reduced frequencies of individual immune cells. We
will gain valuable information regarding the pathways and cell types involved in anti-Nocardia immunity by
performing these analyses. In our second specific aim, we will mine the WES data from the patients in search of
new inborn errors of immunity. To this end, we will perform a genetic analysis combining population genetics,
gene-level, and mutation-level predictive tools to identify mutations that can explain isolated nocardiosis. The
work proposed in this application has far-reaching clinical and biological implications since it will seed light into
the immune and genetic mechanisms critical to fending off Nocardia spp. Biologically, by studying patients with
this rare disease, we will gain basic immunology knowledge of the vital and non-redundant roles of specific cell
types, molecules, and pathways for the proper assembly of human immune responses. Clinically, this
immunological knowledge could be translated into therapies for more common diseases, as has been the case
by studying other PIDs9. Furthermore, our work will pave the way to provide genetic counseling and diagnosis
to patients and families and propose preventive or targeted therapies for individuals at risk. Our proposal
highlights the power of studying rare diseases for the basic and translational information that their study offers.