A sniff to chase ill humors away

Pneumonia is a major cause of death in acute leukemia patients. In this issue of Blood, Leiva-Juárez et al demonstrate a novel way to prevent pneumonia in acute leukemia by inhalation of a synergistic combination of Toll-like receptor 2/6 (TLR 2/6) and TLR9 agonists (Pam2-ODN) to induce protection by bolstering mucosal defenses against challenges by relevant bacterial and mold pathogens.¹  This protection occurred in the setting of neutropenia, despite chemotherapy without exacerbating lung toxicity, in the presence of uncontrolled leukemia, and was associated with rapid pathogen killing mediated by lung epithelial cells. This study extends earlier work by the Evans group studying inducible resistance by lung epithelial cells in in vitro and in animal models.

TLRs are a family of important pattern recognition cell receptors (PRRs) expressed on the membranes of leukocytes and epithelial cells that have roles in the regulation of innate and adaptive immune responses.²  They engage microbes on entering the host by recognition of pathogen-associated molecular patterns. Once engaged, they trigger downstream intermediary signals that lead to elaboration of inflammatory cytokines and other transcription events. Polymorphisms of TLR genes have been recognized to be associated with susceptibility to infection in a variety of medical conditions including acute leukemia³  and after allogeneic hematopoietic cell transplant (HCT).^4-6 

There is a precedent for targeting PRRs therapeutically to bolster anti-infectious protection. Pentraxin 3 (PTX3) is a soluble PRR shown to be important in protection against Aspergillus pneumonia after HCT. In 1 study, a particular genetic variant of PTX3 that was associated with PTX functional deficiency was associated with a doubling of the risk for invasive aspergillosis (IA) after allogeneic HCT.⁷  In a murine HCT model, administration of PTX3 provided protection against the development of IA after an intranasal challenge.⁸ 

These observations remind us that, although the flotilla of hematopoietic cells and circulating molecules that we normally think of providing protection are very important and often determinant in controlling infection, those are not the only host components of innate immunity. The anatomic barriers of skin, mucosa, and lung epithelia make up the first line of defense. These, like the hematopoietic elements, have a repertoire of functions, some of which are inducible and responsive to various signals that can be manipulated to augment protection.

Certainly, we have learned the importance of avoiding breeches in the integument by avoiding venous and urinary catheters and that recognition has led to practice changes to enhance safety. We are beginning to pay attention to the importance maintaining integrity of the gut mucosa, with its associated intestinal immune system, and its interaction with gut microbiota to shape inflammatory responses. This study emphasizes the lung as another opportunity to augment protection to a key portal of entry for microbes.

Our standard approaches to infection prevention have focused on antibiotics to reduce the hordes of microbes threatening at our door, use of myeloid growth factors to shorten neutropenia, and the occasional use of granulocyte transfusions to replace deficiencies of phagocytes. Multiple studies of antibiotics and antifungal drugs have shown their benefits as prophylaxis, with survival advantages in some instances, particularly in acute leukemia. Yet, we now recognize the problems of emergent antibiotic resistance. We are also beginning to see the unintended deleterious consequences of alteration in the gut microbiota that reduces colonization resistance and is associated with increases in systemic infections, graft-versus-host disease, and lower survival after HCT.^9,10  Myeloid growth factors also have a protective role in shortening neutropenia, and granulocyte transfusions may have a role in patients with refractory infections, but they too do not abrogate the risk of infection. If successful, targeting TLRs will not replace these but would be complementary.

There are unanswered questions. Delivery by inhalation is highly desirable but it offers challenges. The delivery device must get the drug to the site of need. Producing the right particle size to reach distal sites in the tracheobronchial tree is crucial. Will this approach be successful with all of the multiple polymorphisms of the TLR molecules or just certain variants? Is there a risk that with certain variants found to be associated with greater risk of infection, there might be an increase in susceptibility? If used after allogeneic HCT, how will this affect risk of graft-versus-host disease?

Studies such as this also suggest additional opportunities. As noted, there are multiple PRRs other than the TLR family. Those too could be targets to exploit. Clearly, more work needs to be done, but this is a good start.