© 2005 The Medicine Publishing Company Ltd 37 : Just when we think we have a good understandi ng of the micro bes that occupy our planet and cause disease, nature reminds us that our knowledge is incomple te. In the last few decades, a n ovel retro- v rus HIV as emerge rom t e unges o A r ca to n ect an kill millions of individuals from all continents. Less dramatically, new y escr e mcro es ave een n e to uman seases since 1980 (Figure 1). Are there other microbial pathoge ns that are significant causes of human disease and await discovery? There are many seases or w c a m cro a ae t oogy s suspecte (Figure 2). The hypothesis that a disease has an infectious cause s supporte y: • clinical featur es – similar to tho se of kno wn infectious diseases e.g. ev er , eucocyto s s • epidemiology – case clustering in time or location • histology – inflammation of affected tissues (e .g. granulomata) or c aracter st c m cro a structures • treatment – a clinical response to antimicr obial treatment • prevent on o seas e y vacc nes targe t ng m cro a ant - ens. Proof that a microbe causes a disease requires more rigorous evidence. If microbes are the cause of some idiopathic diseases, why have we not discovered them yet? • One reason s a ure to cons er t e ypot es s o n ect on. The association between Helicobacter pylori infection and peptic u ce r sease was not ma e un t recent y, esp te our a ty to cultivate this bacterium in the laboratory and to see it under the m cr oscope n gast r c ops es. • Anot er reason s a ure o convent ona mcro a etect on technologies. Studies of bacterial biodiversity in various envi- The infectious aetiology of disease: the search or new agents David N Fredricks David A Relman David N Fredricks is a Member of the Program in Infectious Diseases at Fred Hutchinson Cancer Research Centre and Assistant Professor of Medicine at the University of Washington, Seattle, USA. He qualified from Case Western Reserve University, Cleveland, and tr ained in internal medicine at the University of California, San Francisco and in infectious iseas es at Stan or Univer sity, Stan or . His research interest is t he use of microbial nucleic acid sequences in the detection and identification of novel and uncultivated pathogens. David A Relman is Associate Professor of Medicine and of Microbiology and Immunology at Stanford University, Stanford, USA. He trained in clinical infectious diseases and in molecular microbiology and bacterial pathogenesis. His resear ch interests ar e the discovery of new pathogens, microbial–host interactions and genomics, and the pathogenesis of Bordetella infection. onmental and human niches have shown that cultivation can detect only a fraction of the bacteria identified using nucleic acid sequences. Microbes may exist in viable but non-culturable states, or as sessile members of biofilm communities in which individual ce s may e cu t to cut va te. Accor ng y , a ur e to propagate a microbe in the laboratory does not mean that the sample is free o m cro es. • Microbes ma y evade detection through a pathogenic pr ocess of ‘hit and run’. Organisms such as Streptococcus pyogenes may n t ate an mmuno og ca response t at co nt nues to cause sease long after the microbe is eradicated (rheumatic fever). • U qu to us m cr o es can cause ra re seases as a resut o aberrant host responses. When a common virus causes a rare ne ur o og ca sease n a sma su se t o sus cept e os ts , or example , it is difficult to make an association. Infection with the Some micro-organisms described since 1980 and the diseases they cause • HIV AIDS • Sin Nombre virus Hantavirus pulmonary syndrome • Hepatitis C virus Hepatitis • Human herpesviru s 8 Kaposi’s sarcoma, body cavity-based lymphoma • Nipah virus Encephalitis • SARS coronav rus Severe acute resp ratory syndrome • Escherichia coli O157:H7 Haemolytic uraemic syndrome • Helicobacter pylori Peptic ulcer disease • Bartonella henselae Bacillary angiomatosis, cat-scratch disease • Tropheryma whipplei Whipple’s disease • Ehrlichia chaffeensis Monocyt c erc os s • Anaplasma phagocytophilum Granulocytic ehrlichiosis • Borrelia burgdorferi Lyme disease • Cyclospor a cayatenensis Diarrhoea 1 Idiopathic diseases with a suspected infectious cause • Crohn’s disease • Ulcerative colitis • Brainerd diarrhoea • Mu t p e sc eros s • Kawasaki disease • Rheumatoid arthritis • Wegener’s granulomatosis • Kikuchi–Fugimoto disease • Sarcoidosis • Atherosclerosis • D a etes me tus • Schizophrenia 2
