DR GILLA KAPLAN
Immune responses
Tuberculosis remains a global epidemic to rival any other. Dr Gilla Kaplan describes her
illuminating research into how a comprehensive understanding of tuberculosis as a multiplicity
of strains and host-pathogen interactions could contribute to control of the epidemic
rate of progression of disease, and/or the extent need to do something about it.
of tissue damage.
Does your research have any potential in
Could you describe the current state of elucidating and potentially treating any
global TB infection and treatment: how other diseases? If so, which diseases are
widespread is the disease now and how these and how might the research be applied
urgent is the case to tackle it? to them?
TB is at critical levels: there is probably more Since we work on immunity, we have some
disease now than ever before. There is no interest in the cross-talk between HIV immune
real indication that the control programmes suppression and protection against TB. Some of
that have been in place since the discovery the concepts in the host pathogen interaction
of antibiotics have recently had a major and the cross-talk between the infecting
protective or preventive effect on the agents and the immune response would
disease burden. We try to understand why probably relate to other infectious diseases
this is happening and I think there are three too, including parasitic infections, chronic viral
reasons. One is that TB is simply very difficult infections and other bacterial infections.
to control, even with the multiplicity of
antibiotics that we have. Second is that the Where does your research receive its funding
Firstly, could you outline the primary HIV epidemic in many countries overlaps and how does this affect your work?
objectives of your research and its intended with the TB epidemic and the immune
outcomes? suppression of HIV weakens the immune Most of my funding comes from the NIH:
response which would protect against TB. either individual grants to myself, or being part
In general, I am interested in the host immune That has created a significant increase in of bigger contracts such as the Tuberculosis
response to tuberculosis (TB) and leprosy, and in susceptibility and progression from infection Research Unit contract the NIH holds with a
gaining an understanding of both what regulates to active disease. group of TB investigators. Most of my immune
pathogenesis and of how to modify the immune modulatory work is funded by the Bill and
response to reduce pathogenesis, so the long- Finally, all the years of antibiotic treatment Melinda Gates Foundation and I have also had
term damage from the infection is minimised. – sometimes haphazard and discontinuous small amounts of funding from other sources.
treatment which was not well controlled – has
Diseases like leprosy and TB are caused by given rise to multi-drug resistance. Although Central to the research effort in my lab is a
microbacteria: leprosy by Mycobacterium antibiotics were expected to cure infectious training grant from Fogarty International,
leprae and TB by Mycobacterium tuberculosis diseases and solve the problem, we are losing a component of the NIH, which supports
(MTB). After infection, the major clinical that weapon as the bacteria become resistant training for foreign students and postdocs. The
symptoms are not merely manifestations of to the drugs. And they are doing it faster than grant is specifically targeted for training South
the infection itself, but also of the host immune we can develop new drugs. So we’re going African investigators working in TB research.
response attempting to contain or control it. To back to a time when, in some cases, we cannot This activity keeps us very heavily involved
understand what is happening, you have to look treat TB: for these individuals we’re back in TB researchers in South Africa. Candidates
at the interaction between the bacterium, or where we were before we had antibiotics. That come through the lab, spending anything from
the pathogen, and the host. In that interaction combination of factors has essentially created three to six months here, returning repeatedly.
lies the explanation as to how the immune a significant escalation in the number of cases We help them learn techniques from
response regulates the severity of disease, the and the difficulty of treating TB and the urgent investigators in our own, or other, laboratories.
118 INTERNATIONAL INNOVATION
DR GILLA KAPLAN
Beyond antibiotics
Each year, tuberculosis claims millions of victims worldwide. NIH-funded research is increasing our understanding
of the complex immunological processes which direct the virulence of this disease – and many others
ACCORDING TO THE WHO’s statistics, there by the nature of the host immune response, virulent strain versus the more-virulent strain
were 9.4 million new cases of tuberculosis but also, by characteristics of the bacterium. in the animal models; or the one that induces a
(TB) in 2009. Even this huge number could be After gathering clinical isolates from a range of strong immune response versus the other which
a conservative estimate, according to Dr Gilla patients, the Kaplan lab began testing the extent induces a weak immune response”.
Kaplan, Head of Laboratory, Mycobacterial of strain virulence in the mouse infection model.
Immunity and Pathogenesis at the University of The investigators infected mice with the same Understanding host responses to these clinical
Medicine and Dentistry of New Jersey, whose number of bacilli of different clinical TB isolates, isolates – particularly when HN878 is known
first-hand research experience has given her an closely observing their responses: “What we to be spreading clinically – could have a direct
insight into the scale of this epidemic. Efforts could show was that some strains killed the effect on understanding and better controlling
to contain TB are hindered by a web of factors: mice faster than others; that the strains that the epidemic in humans. At the core of this
the virulence with which the organism causing killed the mice more efficiently induced a weak understanding are the activity levels in key genes
TB – Mycobacterium tuberculosis (MTB) – infects or delayed immune response,” she elucidates. regulating the Th1 protective host immune
its hosts; infections brought about through the Those strains which gained a foothold in the response, much higher in CDC1551 than HN878,
lowered immune responses in those with HIV; host before the immune response could fully rendering the progression and pathogenesis of
and finally the often careless use of antibiotics, react – therefore killing the mice faster – were the disease much more harmful in the later.
which has led in some cases to strains of MTB also those shown recently to be spreading more
which are resistant to one or more drugs (multi efficiently in humans: especially in the HIV-
‘FILLING IN THE GAPS’
drug-resistant). infected population.
The laboratory uses mouse and rabbit models
Treating TB is a lengthy, complex, costly and MTB isolates, through the improvement in of central nervous system (CNS) and pulmonary
potentially painful process, which can take sequencing technology, have recently been infection. There are practical benefits to the
from six to 18 months to clear the infection. shown to be much more diverse than previously widely-used mouse model – such as minimal
Chemotherapy – with its widely-known and thought. While not hugely pronounced, this space taken up in expensive containment
pronounced side effects – is still not definitively diversity is enough to tip the balance in the host- facilities – but also drawbacks, Kaplan explains:
known to be aided by host immunity which is pathogen interaction and therefore induction “To understand the immune response, the mouse
expected to damage bacilli in the lungs; indeed, of immunity and survival of the mice. Kaplan is wonderful because we have all the tools to do
immunity may even drive MTB into a dormant has recently been mostly working with two so. There’s a ‘catch-22’ though: it’s the easiest
state, making the bacilli non-responsive to MTB isolates, CDC1551 and HN878, for specific and best immunologic model available, but not
antibiotics. Through a better understanding of reasons, as she explains: “They have become the the most suitable when it comes to mimicking
MTB and its complex interactions with host hallmark of the less- the clinical picture in humans”.
factors, Kaplan’s laboratory is endeavouring to
work towards more effective treatment in this
and other major infectious diseases.
VARIED VIRULENCE
Due to the variations in severity,
progression and extent of the disease
in different patients, Kaplan’s lab
hypothesised that this diversity
might be contributed to, not only
THE MASIPHUMELELE
TB CLINIC IN
SOUTH AFRICA
WWW.RESEARCHMEDIA.EU 119
INTELLIGENCE The rabbit model differs in that the animals together with Celgene scientists, developed
are larger and more expensive to house, but two classes of novel, synthetic analogues of
ANALYSIS OF XDR-TB AND MDR-TB
this model displays a disease process which is thalidomide that reduce TNF-α production by
STRAINS: SAFETY, DIAGNOSIS AND
much more like human TB. MTB infected rabbits up to 50,000 times more than the parent drug
PATHOGENESIS
develop granulomas in the lung. These structures and with fewer deleterious side effects. Some of
OBJECTIVES are aggregates of uninfected as well as MTB these molecules are already extensively used to
TB control is increasingly compromised infected cells that become centrally necrotic treat haematologic cancers and others are being
by the global rise in HIV-induced immune and can develop cavities. These structures are examined for efficacy in chronic inflammatory
suppression and in M/XDR-TB. Effective M/ the hallmark of human TB. Taking the best from and autoimmune diseases. This, Kaplan believes,
XDR-TB epidemiologic surveys and case each model to gain the most comprehensive has been a major achievement in their work: “The
management, as well as the development of understanding of host-pathogen interaction development of thalidomide and thalidomide
new diagnostics and anti-TB drugs, require is crucial: “From a pathology point of view, analogues for clinical indications in humans has
strong laboratory capabilities. For example, the rabbit is much more like the human, but been a fantastic journey. It has made not only a
defining drug resistance profiles in patients assessing the immune response in rabbits is much major contribution clinically, but has also been
undergoing TB therapy is an area which Dr more difficult. Ultimately,” Kaplan continues, “we a major economic success for the company”.
Kaplan is seeking to address. do both, so that we can fill in the gaps and know Kaplan is now turning her attention to the use
that we are looking at a picture that adds up to of these drugs in infectious disease such as TB.
KEY COLLABORATORS something more like human disease”. “All of that is based on work done in our lab,” she
Clifton E. Barry III, PhD, National Institute enthuses.
of Health, Maryland, USA • Henry Boom, Alongside these in vivo animal models, Kaplan’s
MD, Case Western Reserve University, Ohio, New Jersey laboratory conducts basic in vitro
TB VACCINES AND OTHER
USA • David Russell, PhD, Cornell University, analyses of cell responses to MTB infection.
PATIENT STUDIES IN SOUTH AFRICA
New York, USA • Linda-Gail Bekker-Wood, Members of the lab study the activation of the
MD, PhD, Desmond Tutu HIV Centre, monocytes at the early stages of infection, In addition to Kaplan’s studies at the Public
University of Cape Town, Cape Town, South assessing the response to different strains, and Health Research Institute, she has a number
Africa • Gerrit Coetzee, MD, National Health how they are regulated at the cellular level. Of of off shore collaborative studies in human
Laboratory Services, Johannesburg, South course, to obtain a full understanding of host- populations being conducted at the University
Africa • Clive Gray, MD, University of Cape pathogen interactions, paying attention to the of Cape Town, Cape Town, South Africa. The
Town, Cape Town, South Africa • Willem MTB organism itself is vital, Kaplan tells us: “We pathogenic process that occurs in the lung of TB
Hanekom, MD, University of Cape Town, also do quite a lot of work on understanding the patients is being analysed together with Dr David
Cape Town, South Africa differences between the bacterial strains, which Russell, and the effect of antiretroviral treatment
properties cause disease, how the different of HIV infected individuals on TB disease and MTB
FUNDING strains are spreading in the population, how they transmission are being studied in collaboration
NIH-NIAID – National Institutes of Health- acquired drug resistance and so on,” she outlines. with Dr Linda-Gail Bekker Wood. In addition,
National Institute of Allergy and Infectious immunologic correlates of BCG vaccination-
Diseases • NIH-GID National Institutes of induced protective immunity against TB disease
THALIDOMIDE ANALOGUES
Health/John E Fogarty International Center- in infants are being defined in collaboration with
Global Infectious Disease Research Training In studying a condition called Erythema Dr Willem Hanekom and Dr Henry Boom. Kaplan
Program • NIH-NIAID – DMID/TBRU • Nodosum Leprosum (ENL) in leprosy patients, has recently begun a study to explore host and
NIH-NIAID – Division of Microbiology and Kaplan’s earlier work led her to investigate pathogen factors that contribute to the failure
Infectious Diseases/Tuberculosis Research thalidomide – a sedative introduced in the of treatment of MDR TB, ultimately leading to
Unit • BMGF – Bill and Melinda Gates 1950s and withdrawn in the 60s after it was emergence of XDR TB strains in HIV-infected and
Foundation found to cause birth defects if used by pregnant non-HIV-infected patients in collaboration with
women. The drug was later found to be useful in Drs Gerrit Coetzee and Clive Gray of the National
CONTACT treating patients with ENL. Through exploring Health Laboratory Services and the University
Dr Gilla Kaplan which aspects of the immune response were Cape Town, South Africa. Similar studies have
Public Health Research Institute Center responding to thalidomide, Kaplan made a crucial also been initiated in collaboration with Dr Clif
observation: “We discovered that thalidomide Barry in China.
University of Medicine and Dentistry
inhibited or reduced – but not ablated – the
of New Jersey
production of one of the soluble hormones which
225 Warren Street, Newark, PUBLISH OR PERISH
drives and regulates the immune response – a
New Jersey 07103-3535, USA
molecule known as tumor necrosis factor-alpha For the purpose of seeking partners and funding
T +1 973 854 3220 (TNF- α)”. This molecule plays a central role in in her research ventures, Kaplan has no doubt
E kaplangi@umdnj.edu the immune response to many diseases but too that dissemination of research results is vital:
much TNF-α causes severe pathology. So being “You don’t get funded if you don’t publish: it’s
http://www.phri.org/research/res_ able to down-regulate, or modify the TNF-α ‘publish or perish’. Also getting your results into
pikaplan.asp response could provide a groundbreaking tool the public domain is very important to inform
for alleviating disease/pathology in conditions as other scientist about your studies”.
DR KAPLAN is Professor of Medicine and diverse as cancers, serious chronic inflammatory
head of the Laboratory of Mycobacterial disorders and infectious diseases. Encouragingly, through her research and that of
Immunity and Pathogenesis at the Public others, Kaplan believes we are reaching a point
Health Research Institute Center at UMDNJ. Overcoming the challenges of gaining permission of really understanding the ‘cross-talk’ in host-
She received her BSc from the Hebrew from the FDA, as well as seeking someone to pathogen interaction, and opening up new insight
University in Jerusalem, Israel and her MSc synthesise the drug and get it approved for use into how ‘resetting’ the immune system and
and PhD from the University of Tromso in the U.S. – which she found in the partner establishing a new and advantageous balance
in Norway. She worked at the Rockefeller company Celgene Corporation – Kaplan, could contribute to controlling TB.
University, New York City as a faculty member
for 19 years before moving to PHRI in 2002.
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