# Validation and Application of a Model for Human-like TB Latency in Rabbits

> **NIH NIH U19** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $525,694

## Abstract

Project 2 will validate a model of human-like TB latency in New Zealand White rabbits, and apply this model
to test interventions against latent TB infections (LTBl). The world's latently infected population comprises
the reservoir which feeds the global tuberculosis TB epidemic. Novel approaches to treat latent infections
would contribute greatly to TB eradication. There is a critical need to develop an animal model that reflects
the human spectrum of latency. The mouse is a poor model for LTBl; and our preliminary data and work by
others suggests that "latently-infected" non-human primates are more likely "percolators" with significantly
more bacterial replication and mutational stress than is seen with LTBl in humans. Rabbits infected with
Mycobacterium tuberculosis (Mtb) strain CDC1551 develop a primary infection that is rapidly contained, after
which the Mtb bacilli soon become undetectable in all rabbit tissues. Yet, like human latency, low numbers of
Mtb bacilli persist in an undetectable (latent) state because they can be reactivated by immune suppression
with corticosteroids. We will more fully study the range of bacterial activity that occurs in human latency at
our clinical site in Vitoria, Brazil. These results will be used to benchmark, and if needed, fine tune (modify)
our rabbit latency model. Next, we will use infections with a high-density bar-code Mtb library to measure (for
the first time) the rate of Mtb cell killing during latency, the number of clones that survive during LTBl, and
the replication and mutation rate during this disease state. We will then use high-density bar-coded Mtb to
map the pathway of clonal re-emergence during reactivation. Mtb gene knockouts will be used to identify
bacterial factors essential for latency LTBl. The rabbit latency model, bar-coded library and latency
knockouts will then be used as tools to evaluate the efficacy of new therapeutic interventions in eradicating
paucibacillary infection. Correlates of immunological protection identified in human TB in Project 1 will be
queried in these efficacy studies. Cross-fertilizing with Project 4, we will establish the overlap between
bacterial factors required for persistence vs. latency. The discovery of novel latency and persistence genes
will identify new druggable targets active against the latent state.

## Key facts

- **NIH application ID:** 10004559
- **Project number:** 5U19AI111276-08
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** David Alland
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $525,694
- **Award type:** 5
- **Project period:** 2014-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004559

## Citation

> US National Institutes of Health, RePORTER application 10004559, Validation and Application of a Model for Human-like TB Latency in Rabbits (5U19AI111276-08). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10004559. Licensed CC0.

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