Intercellular adhesion molecules (ICAMs) belong to the immunoglobulin 
superfamily and participate in diverse cellular processes including 
host-pathogen interactions. ICAM-1 is expressed on various cell types including 
macrophages, whereas ICAM-4 is restricted to red blood cells. Here we report the 
identification of an 11-kDa synthetic protein, M5, that binds to human ICAM-1 
and ICAM-4, as shown by in vitro interaction studies, surface plasmon resonance 
and immunolocalization. M5 greatly inhibits the invasion of macrophages and 
erythrocytes by Mycobacterium tuberculosis and Plasmodium falciparum, 
respectively. Pharmacological and siRNA-mediated inhibition of ICAM-1 expression 
also results in reduced M. tuberculosis invasion of macrophages. ICAM-4 binds to 
P. falciparum merozoites, and the addition of recombinant ICAM-4 to parasite 
cultures blocks invasion of erythrocytes by newly released merozoites. Our 
results indicate that ICAM-1 and ICAM-4 play roles in host cell invasion by M. 
tuberculosis and P. falciparum, respectively, either as receptors or as crucial 
accessory molecules.