Understanding the role of inflammatory cytokines in malaria and related diseases

Summary

It is now broadly accepted for infectious disease in general that it is not the invading organism, but the body's unbridled response to it—the “cytokine storm”—that causes illness and pathology. Nevertheless, many researchers still regard the harmful effects of falciparum malaria as being governed by oligaemic hypoxia arising from parasitised erythrocytes obstructing blood flow through vulnerable organs, particularly the brain, and we summarise why these notions are no longer tenable. In our view, this harmful sequestration is readily accommodated within the cytokine storm perspective as one of its secondary effects. We approach these issues by examining aspects of malaria, sepsis and influenza in parallel, and discuss the insights that comparisons of the literature can provide on the validity of possible anti-disease therapies.

Introduction

Falciparum malaria is one of the dominant human infectious diseases, a cause of massive social and economic disruption¹ as well as morbidity and mortality.² Yet how it actually kills patients, the focus of this review, is a hotly disputed topic. Before discussing how this particular parasitic disease might be causing harm, it warrants noting that the common practice of drawing tight boundaries between individual illnesses, and between disease and basic research, often excludes critical insights with broad implications. Our intention is to help redress this balance. Indeed, the main lesson the past few decades of intense activity in this field have taught some of us has been how intellectually limiting it can be to place infectious, or parasitic (terms best equated, from a pathophysiology aspect), illnesses into categories based on the size of the pathogen. All the literature on the effects of infectious agents ranging in size from those responsible for influenza and trichinosis, passing through bacteria and protozoa, nowadays has its inflammatory cytokine stories to tell. We will, therefore, draw from basic science as well as research on sepsis, influenza and malaria.

Systemic inflammation, characterised by the release of a wide range of pro- and anti-inflammatory polypeptides, termed cytokines, into the circulation, is not just the preserve of diseases initiated by pathogens. As recently reviewed,³ systemic inflammation also occurs in certain non-infectious disease states, some iatrogenic. The general view of the pathogenesis of infectious disease has undergone a paradigm change in the past few decades, particularly in the past 5 years or so in which the term “cytokine storm” has become popular currency.⁴ In brief, it seems now to have been broadly accepted that it is not the invading organism, but the body's unbridled response to it, that causes the disease we associate with the infectious agent. It is central to this conceptual approach that these host-origin cytokines, induced by the infectious agent (although sometimes indirectly: see the ingenious RIG-I argument in influenza⁵), also mediate innate immunity, and probably evolved for this purpose.⁶

The new approaches to malaria disease owe an increasing debt to other branches of science. Awareness of TNF, for example, arose in a group who were trying to understand how Bacillus Calmette Guérin (BCG) and lipopolysaccharide (LPS) protected against tumours. This opened a door into explaining how BCG protected against haemoprotozoa, and thence to bacterial and viral diseases.⁷ Unfortunately, the subsequent, and illuminating, two way traffic that has developed between malaria and other diseases that are the consequences of infectious agents is still largely ignored by those who instinctively put diseases caused by different organisms in different baskets. In this review we discuss aspects of falciparum malaria, bacterial sepsis and influenza, and note what we can learn from their commonalities.