Increased TIMP Levels in Malaria Patients: Risk or Protective Factors?

Dipartimento di Neuroscienze, Università di Torino, Torino, Italy

*Corresponding Author:

Prof. Mauro Prato, Ph.D
Dipartimento di Neuroscienze, Universitá di Torino
Corso Raffaello 30, 10125, Torino, Italy
Tel: +39-011-6708198
Fax: +39-011-6708174
E-mail: mauro.prato@unito.it

Received Date: October 17, 2013; Accepted Date: October 18, 2013; Published Date: October 25, 2013

Citation: Prato M (2013) Increased TIMP Levels in Malaria Patients: Risk or Protective Factors? Air Water Borne Diseases 2:e123. doi:10.4172/2167-7719.1000e123

Copyright: © 2013 Prato M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Visit for more related articles at Air & Water Borne Diseases

Despite the recent decline in estimated malaria cases and deaths - 655.000 deaths among more than 200 million clinical cases worldwide registered in 2010 by World Health Organization (WHO) [1] - malaria remains so far an alarming emergency in developing countries, including Africa and South-East Asia. Thus, it appears urgent to identify new affordable markers for early diagnosis of malaria complications and new targets for primary and adjuvant therapy.

Recently, it has come to light that Tissue Inhibitors of Metalloproteinases (TIMPs) are involved in malaria disease state. These molecules were originally characterized as endogenous Matrix MetalloProteinase (MMP) inhibitors, thus playing a key role in turnover of extracellular matrix and shedding of cell surface molecules [2]. Additionally, TIMPs have important roles in a broad spectrum of MMP-independent biological activities, including cell survival, cell growth and differentiation, cell migration, angiogenesis, and synaptic plasticity [3,4].

Currently, our understanding of TIMPs in malaria manifests from only a few studies showing dysregulated TIMP levels in different in vitro and in vivo malaria models. In human adherent monocytes cultured in vitro, nHZ (a lipid-bound ferriprotoporphyrin IX crystal produced by Plasmodium parasites after haemoglobin catabolism) induced inflammation-mediated expression and release of TIMP-1 through p38 MAPK- and NF-κB-dependent mechanisms [5], without affecting TIMP-2 production [6]. In human microvascular endothelial cells, either P. falciparum-IRBCs or nHZ promoted TIMP-2 but not TIMP-1 protein release [7,8]. in vivo, CM-sensitive mice infected with P. berghei ANKA displayed increased mRNA expression of TIMP- 1 in the brain, and both TIMP-1 and -3 mRNA was increased in the liver and spleen, whilst mRNA levels of TIMP-2 and -4 remained unchanged [9]. Increased serum levels of TIMP-1 were also found in Rhesus macaques (Macaca mulatta) experimentally infected with P. coatneyi, a simian malaria parasite that closely mimics the biological characteristics of P. falciparum and replicates the multisystemic dysfunction of human severe malaria [10]. Finally, human patients with severe or uncomplicated malaria displayed higher serum TIMP-1 levels compared to healthy controls, thus suggesting a potential role for TIMP-1 as a diagnostic marker [11].

Still, it is not clear whether higher TIMP levels in malaria patients should be considered protective or risk factors. In this context, the case of TIMP-1 is paradigmatic. One major function of TIMP-1 is to counteract and modulate the numerous effects of MMP-9, which include degradation of the sub-endothelial basal lamina, modulation of the activity of several pro-inflammatory molecules, disruption of tight junctions, and impairment of haemostasis [2], all of which comprise key roles in CM. Thus, it is attractive to hypothesize that increased TIMP-1 levels are a protective factor in malaria prognosis, as they could contrast the potentially detrimental effects of nHZ-enhanced MMP-9 [12]. However, in vitro MMP-9/TIMP-1 stoichiometric ratios and total gelatinolytic activity measured in nHZ-fed monocyte supernatants have been shown to be significantly higher than in controls, suggesting that nHZ-dependent induction of TIMP-1 is not sufficient to counterbalance nHZ-enhanced MMP-9 levels, and arguing against TIMP-1 ability to act as a protective factor in this context [5]. What is more, in vivo TIMP-1 serum levels correlated with disease severity in Gabonese children with malaria, suggesting a potential role for TIMP-1 as a risk factor [11].

Intriguingly, TIMP-1 could play a detrimental role through an MMP-independent mechanism. MMP-independent roles for TIMP- 1 in biological processes include anti-apoptotic effects of TIMP-1 in several human cells, such as Burkitt’s lymphoma, breast epithelial cells, and cardiomyocytes [3,4]. Recently CD63, a member of the tetraspanin family, was identified as a cell-binding partner for TIMP-1 in human mammary epithelial cells, and CD63 down-regulation with shRNA resulted in reduced TIMP-1 binding and restored cell apoptosis [13]. Interestingly, nHZ-fed monocytes do not undergo apoptosis, despite increased inflammation and functional impairment [14,15]. Since CD63 is constitutively expressed by human monocytes [16], it is intriguing to speculate that nHZ-enhanced TIMP-1 levels might prevent apoptosis of functionally impaired nHZ-fed cells through CD63-dependent mechanisms. Additionally, there are several reports describing MMP-independent abilities of TIMP-1 to inhibit cell growth and differentiation [3,4]. These TIMP-1 properties may be crucial for nHZ-fed monocytes, since these cells have been shown not to mature to dendritic cells [17] and not to coordinate erythropoiesis [18].

Future investigation is needed to ascertain whether enhanced TIMP levels may contribute to worsen the clinical course in malaria patients as a consequence of their MMP-independent anti-apoptotic or growth/differentiation-inhibitory properties. Therefore, more extensive research on the functional role of TIMPs in malaria, along with a better understanding of MMP-independent TIMP functions will be welcomed in order to find new tools for differential diagnosis and therapy of severe malaria.

References

1. WHO (2011) World Malaria Report 2011
2. Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69: 562-573.
3. Chirco R, Liu XW, Jung KK, Kim HR (2006) Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev 25: 99-113.
4. Stetler-Stevenson WG (2008) Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal 1: re6.
5. Polimeni M, Valente E, Ulliers D, Opdenakker G, Van den Steen PE, et al. (2013) Natural haemozoin induces expression and release of human monocyte tissue inhibitor of metalloproteinase-1. PLoS One 8: e71468.
6. Prato M (2011) Malarial pigment does not induce MMP-2 and TIMP-2 protein release by human monocytes. Asian Pac J Trop Med 4: 756.
7. Prato M, D'Alessandro S, Van den Steen PE, Opdenakker G, Arese P, et al. (2011) Natural haemozoin modulates matrix metalloproteinases and induces morphological changes in human microvascular endothelium. Cell Microbiol 13: 1275-1285.
8. D'Alessandro S, Basilico N, Prato M (2013) Effects of Plasmodium falciparum-infected erythrocytes on matrix metalloproteinase-9 regulation in human microvascular endothelial cells. Asian Pac J Trop Med 6: 195-199.
9. Van den Steen PE, Van Aelst I, Starckx S, Maskos K, Opdenakker G, et al. (2006) Matrix metalloproteinases, tissue inhibitors of MMPs and TACE in experimental cerebral malaria. Lab Invest 86: 873-888.
10. Moreno A, Cabrera-Mora M, Garcia A, Orkin J, Strobert E, et al. (2013) Plasmodium coatneyi in rhesus macaques replicates the multisystemic dysfunction of severe malaria in humans. Infect Immun 81: 1889-1904.
11. Dietmann A, Helbok R, Lackner P, Issifou S, Lell B, et al. (2008) Matrix metalloproteinases and their tissue inhibitors (TIMPs) in Plasmodium falciparum malaria: serum levels of TIMP-1 are associated with disease severity. J Infect Dis 197: 1614-1620.
12. Khadjavi A, Valente E, Giribaldi G, Prato M (2013) Involvement of p38 MAPK in haemozoin-dependent MMP-9 enhancement in human monocytes. Cell Biochem Funct.
13. Jung KK, Liu XW, Chirco R, Fridman R, Kim HR (2006) Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO J 25: 3934-3942.
14. Giribaldi G, Prato M, Ulliers D, Gallo V, Schwarzer E, et al. (2010) Involvement of inflammatory chemokines in survival of human monocytes fed with malarial pigment. Infect Immun 78: 4912-4921.
15. Prato M, Gallo V, Valente E, Khadjavi A, Mandili G, Giribaldi G (2010) Malarial pigment enhances Heat Shock Protein-27 in THP-1 cells: new perspectives for in vitro studies on monocyte apoptosis prevention. Asian Pac J Trop Med 3: 934-938.
16. Pols MS, Klumperman J (2009) Trafficking and function of the tetraspanin CD63. Exp Cell Res 315: 1584-1592.
17. Urban BC, Todryk S (2006) Malaria pigment paralyzes dendritic cells. J Biol 5: 4.
18. Giribaldi G, Ulliers D, Schwarzer E, Roberts I, Piacibello W, et al. (2004) Hemozoin- and 4-hydroxynonenal-mediated inhibition of erythropoiesis. Possible role in malarial dyserythropoiesis and anemia. Haematologica 89: 492-493.