Full Text PA-97-085
 
THE LATENT STATE IN TUBERCULOSIS INFECTION
 
NIH GUIDE, Volume 26, Number 24, July 25, 1997
 
PA NUMBER:  PA-97-085
 
P.T.


Keywords: 

 
National Institute of Allergy and Infectious Diseases
National Heart, Lung, and Blood Institute
 
PURPOSE
 
The National Institute of Allergy and Infectious Diseases (NIAID)and
National Heart, Lung, and Blood Institute (NHLBI) National Institutes
of Health (NIH), invite applications that propose to investigate the
"latent" phase of infection by Mycobacterium tuberculosis (M.tb) and
the mechanism(s) by which M.tb is reactivated in some hosts.  For the
purposes of this initiative, "the latent state" refers to that state
of infection during which clinical disease is inapparent, yet
infection of the host has been established.  The mechanisms by which
this phase terminates in some hosts and persistent bacilli are
re-activated, leading to development of active disease, are also of
interest.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This PA,"
THE LATENT STATE IN TUBERCULOSIS INFECTION" is related to the
priority area(s) of Immunization and Infectious Diseases, and HIV
Infection. Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 017-001-00474-0 or Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone
202-512-1800).
 
ELIGIBILITY
 
Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Foreign institutions are not eligible for FIRST awards (R29).
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
 
MECHANISM OF SUPPORT
 
Traditional research project grant (R01) and FIRST award
(R29) applications may be submitted in response to this program
announcement).  Applications for R01 grants may request up to five
years of support; applications for R29 grants must request five years
of support.  Responsibility for the planning, direction, and
execution of the proposed research for all applicable mechanisms of
support will be solely that of the applicant.
 
RESEARCH OBJECTIVES
 
Background
 
Tuberculosis remains the most prevalent cause of death due to a
single infectious pathogen in the world today.  Not only do an
estimated 3 million persons die annually of tuberculosis, but one-
third of the world's population is believed to be currently infected
with the causative agent, M.tb. This apparently healthy population,
although not currently infectious,  represents a vast reservoir of
potential future transmitters. It has been estimated that ten percent
of
immunocompetent, infected persons will develop active disease during
their lifetime, and 8-9% of those who are immunocompromised by
concurrent HIV infection will develop active tuberculosis per year,
thereby becoming capable of transmitting M.tb to others. The extended
course of therapy required for adequate treatment of even
drug-susceptible strains of M.tb is necessitated by the difficulty of
eradicating persistent bacilli.  Current drugs kill actively growing
M.tb within days, but months of therapy are needed to fully eliminate
the persistent organisms.
 
Despite the enormous impact on public health of the latent phase of
M.tb infection, little is known about the biology of the bacterium
during this stage of infection, the bacillus-host interaction, the
immunologic parameters that are involved in establishing persistent
infection, or the mechanisms of pathogen and host that lead to
reactivation of M.tb and development of active disease.  This lack of
understanding is reflected in a dearth of effective immunologic and
chemotherapeutic tools to treat latent M.tb infection or prevent
reactivation.
 
Research Objectives and Scope
 
NOTE:  Three complementary Program Announcements are being issued:
"The Latent State in Tuberculosis Infection"; "Tuberculosis - Basic
Biology, Immunology and Pathogenesis"; and "Innovative Approaches to
Investigating Human Tuberculosis".
 
Applications which focus on understanding the latent state in
tuberculosis infection and/or reactivation of tuberculosis should be
submitted in response the PA "The Latent State in Tuberculosis
Infection".  Applications which focus on the use of model systems and
or mycobacterial species other than M.tb to further understanding of
any other aspect of tuberculosis should be submitted in response to
the PA "Tuberculosis - Basic Biology, Immunology and Pathogenesis";
and applications which primarily focus on use of M.tb and/or human
cells, tissues or study populations to study any aspect of human
tuberculosis, per se, other than latency/reactivation should be
submitted in response to the PA "Innovative Approaches to
Investigating Human Tuberculosis".
 
The subject of latency is currently a key gap in tuberculosis
research programs funded by NIAID and NHLBI.  We aim to remedy this
situation by encouraging applications that focus on the molecular
basis of latency and development of effective tools for diagnosing,
treating and intervening against the latent state.  These include,
but are not limited to, applications addressing:
 
o  host and/or bacterial mechanisms and processes that cause or are
involved in entry into the latent state, including definition of the
regulatory genes and factors responsible;
 
o  biology, biochemistry and physiology of the bacterium during
latency, including identification of genes and their products
responsible for or important to the maintenance of latency;
 
o  microbial regulatory factors that repress latency and lead to
establishment of active disease;
 
o  possible role(s) of immunologic factors/mechanisms in
establishing, maintaining and repressing latency;
 
o  development/improvement of animal models reflective of latency in
human tuberculosis;
 
o  development of skin test(s) or other diagnostic tool(s) that can
distinguish latent infection from BCG vaccination from active
disease;
 
o  development of therapeutic agents effective against latent
bacteria;
 
o  development of anti-TB vaccine candidates capable of conferring
protective efficacy against latent organisms by, for example,
blocking reactivation and/or subsequent transmission; development of
"post-exposure" animal models suitable for evaluating such vaccine
candidates.
 
Whole genome approaches, capitalizing on the availability of M.tb
genomic sequence, are encouraged where appropriate.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification are
provided that inclusion is inappropriate with respect to the health
of the subjects of the purpose of the research.  This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43).
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and the NIH
Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994.
 
Investigators may obtain copies from these sources or from the
program staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application for PHS 398
(rev. 5/95) and will be accepted on the standard application
deadlines as indicated in the application kit.
 
Application kits are available at most institutional offices of
sponsored research and may be obtained from the Office of Extramural
Outreach and Information, National Institutes of Health, 6701
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301)
435-0714, email: asknih@odrockm1.nih.gov.
 
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES".  The PA number and the
PA title must also be typed in section 2.
 
The completed, signed original and five legible, single-sided copies
of the application and any appendices must be sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)
 
R29 APPLICANTS ONLY.  R29 applications must include at least three
(3) sealed letters of reference attached to the face page of the
original application.  FIRST applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
ALL APPLICANTS REQUESTING $500,000 OR MORE IN ANNUAL DIRECT COSTS.
The NIH Policy Update on Acceptance for Review of Unsolicited
Applications that Request More Than $500,000 Direct Cost for Any One
Year applies to applications in response to this PA.  The Policy
Update was published in the NIH Guide for Grants and Contracts,
Volume 25, No. 14, May 3, 1996, and became effective June 1, 1996.
 
Potential applicants must contact the appropriate program staff
listed in INQUIRIES below to initiate clearance processes for
acceptance of their applications.
 
GCRC INSTITUTIONS
 
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
material.
 
REVIEW CONSIDERATIONS
 
Review Procedures
 
Applications will be assigned on the basis of established PHS
referral guidelines. Upon receipt, applications will be reviewed for
completeness by the NIH Division of Research Grants.  Incomplete
applications will be returned to the applicant without further
consideration.
 
Applications will be reviewed for scientific and technical merit by
study sections of the Division of Research Grants, NIH, in accordance
with the standard NIH peer review procedures. As part of the initial
merit review, all applications will receive a written critique and
undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of the applications
under review, will be discussed, assigned a priority score, and
receive a second level review by the appropriate national advisory
council.
 
Review Criteria
 
The five criteria to be used in the evaluation of grant applications
are listed below.
 
The goals of NIH-supported research are to advance our understanding
of biological systems, improve the control of disease, and enhance
health.  The reviewers will comment on the following aspects of the
application in their written critiques in order to judge the
likelihood that the proposed research will have a substantial impact
on the pursuit of these goals.  Each of these criteria will be
addressed and considered by the reviewers in assigning the overall
score weighting them as appropriate for each application.  Note that
the application does not need to be strong in all categories to be
judged likely to have a major scientific impact and thus deserve a
high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is
essential to move a field forward.
 
1.  Significance.  Does this study address an important problem? If
the aims of the application are achieved, how will scientific
knowledge be advanced?  What will be the effect of these studies on
the concepts or methods that drive this field?
 
2.  Approach.  Are the conceptual framework, design, methods, and
analyses adequately developed, well-integrated, and appropriate to
the aims of the project?  Does the applicant acknowledge potential
problem areas and consider alternative tactics?
 
3.  Innovation.  Does the project employ novel concepts, approaches
or method?  Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies?
 
4.  Investigator.  Is the investigator appropriately trained and well
suited to carry out this work?  Is the work proposed appropriate to
the experience level of the principal investigator and other
researchers (if any)?
 
5.  Environment.  Does the scientific environment in which the work
will be done contribute to the probability of success?  Do the
proposed experiments take advantage of unique features of the
scientific environment or employ useful collaborative arrangements?
Is there evidence of institutional support?
 
The initial review group will also examine: the appropriateness of
proposed project budget and duration; the adequacy of plans to
include both genders and minorities and their subgroups as
appropriate for the scientific goals of the research and plans for
the recruitment and retention of subjects; the provisions for the
protection of human and animal subjects; and the safety of the
research environment.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other
favorably recommended applications.  The following will be considered
when making funding decisions: quality of the proposed project as
determined by peer review, program balance among research areas of
the announcement, and availability of funds.
 
INQUIRIES
 
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Inquiries regarding programmatic issues may be directed to Dr. Ann M.
Ginsberg at NIAID and Dr. Hannah H. Peavy at NHLBI:
 
Ann M. Ginsberg, MD, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3B06
6003 Executive Blvd.
Bethesda, MD 20892-7630
Telephone: (301) 496-5305
Fax:       (301) 496-8030
EMAIL:     ag73i@nih.gov
 
Hannah H. Peavy, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Two Rockledge Centre, Suite 10018, MSC 7952
6701 Rockledge Drive
Bethesda, Maryland 20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
E-mail: hannah_peavy@nih.gov
 
Direct inquiries regarding fiscal matters to Ms. Catherine Walker,
NIAID and Mr. Raymond L. Zimmerman, NHLBI:
 
Ms. Catherine Walker
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B32
6003 Executive Blvd.
Bethesda, MD  20892-7610
Telephone: (301)402-7146
Fax: (301)480-3780
Email: cwalker@mercury.niaid.nih.gov
 
Raymond L. Zimmerman
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Centre, Suite 7154, MSC 7926
6701 Rockledge Drive
Bethesda, MD 20892-79??
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
E-mail: raymond_zimmerman@nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is supported under authorization of the Public Health
Service Act, Sec. 301(c), Public Law 78-410, as amended.  The
Catalogue of Federal Domestic Assistance Citations are No. 93.838.
and No. 93.856.
 
Awards will be administered under PHS grants policies and Federal
Regulations 42 CFR Part 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems review.
 
The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.
 
.

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